Remedies for diseases with bone mass loss having ep4 agonist as the active ingredient

ABSTRACT

A pharmaceutical composition for topical administration for prevention and/or treatment of diseases associated with decrease in bone mass comprising an EP 4  agonist as an active ingredient. An EP 4  agonist, in which includes a compound possessing prostaglandin skeleton as a representative, possesses promoting action on bone formation, so it is useful for prevention and/or treatment of diseases associated with decrease in bone mass (bone diseases such as primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget&#39;s disease, bone loss and bone necrosis, postoperative osteogenesis, alternative therapy for bone grafting).

TECHNICAL FIELD

The present invention relates to

-   (1) a pharmaceutical composition for topical administration for    prevention and/or treatment of diseases associated with decrease in    bone mass comprising an EP₄ agonist as an active ingredient,-   (2) a sustained release formulation comprising the agonist as an    active ingredient,-   (3) a prostaglandin derivative of formula (I-2)    -   (wherein all symbols have the same meaning as defined        hereinafter),    -   or a non-toxic salt thereof, or a cyclodextrin clathrate        thereof, and a process for the preparation thereof and a        pharmaceutical composition comprising thereof as an active        ingredient,-   (4) an 8-azaprostaglandin derivative of formula (I-3)    -   (wherein all symbols have the same meaning as defined        hereinafter),    -   or a non-toxic salt thereof, or a cyclodextrin clathrate        thereof, and a process for the preparation thereof and a        pharmaceutical composition comprising thereof as an active        ingredient, and-   (5) a compound selected from the group consisting of-   (1)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (2)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (3)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (4)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (5)    (15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (6)    (15α,13E)-9-Oxo-15-hydroxy-16-(4-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (7)    (15α,13E)-9-Oxo-15-hydroxy-16-(2-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (8)    (15α,13E)-9-Oxo-15-hydroxy-16-(2-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (9)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (10)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (11)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (12)    (15α,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (13)    (15α,13E)-9-Oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (14)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (15)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-ethoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (16)    (15α,13E)-9-Oxo-15-hydroxy-16-(3-isopropyloxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (17)    (15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (18)    (15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (19)    (15α,13E)-9-Oxo-15-hydroxy-16-(3,5-dimethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (20)    (15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (21)    (15α,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (22)    (15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (23)    (15α,5Z,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (24)    (15α)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprostanoic    acid and-   (25)    (15α,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoic    acid 3-phenylphenyl ester,    -   or a non-toxic salt thereof, or a cyclodextrin clathrate        thereof, and a process for the preparation thereof and a        pharmaceutical composition comprising thereof as an active        ingredient.

BACKGROUND ART

Prostaglandin E₂ (abbreviated as PGE₂) has been known as a metabolite inthe arachidonate cascade. It has been known that PGE₂ possessescyto-protective activity, uterine contractive activity, a pain-inducingeffect, a promoting effect on digestive peristalsis, an awakeningeffect, a suppressive effect on gastric acid secretion, hypotensiveactivity and diuretic activity and so on.

A recent study has proved existence of various PGE subtype receptorspossessing a different physical role from each other. At present, fourreceptor subtypes are known and they are called EP₁, EP₂, EP₃, and EP₄(Negishi M., et al., J. Lipid Mediators Cell Signaling, 12, 379-391(1995)).

It is thought that EP₄ subtype receptor relates to inhibition ofproducing TNF-α and acceleration of producing IL-10. Therefore, thecompounds which can bind on EP₄ subtype receptor are expected to beuseful for the prevention and/or treatment of immunological diseases(autoimmune diseases such as amyotrophic lateral sclerosis (ALS),multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis andsystemic lupus erythematosus etc., and rejection after organtransplantation etc.), asthma, neuronal cell death, arthritis, lungfailure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronicobstructive pulmonary disease, liver damage, acute hepatitis, nephritis(acute nephritis, chronic nephritis), renal insufficiency, hypertension,myocardiac ischemia, systemic inflammatory response syndrome, sepsis,hemophagous syndrome, macrophage activation syndrome, Still's disease,Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis,Crohn's disease, hypercytokinemia at dialysis, multiple organ failure,and shock etc.

It is also thought that EP₄ subtype receptor relates to protecting ofmucosa. Therefore, the compounds which can bind on EP₄ subtype receptorare expected to be useful for the prevention and/or treatment of ulcerof gastrointestinal tract such as gastric ulcer and duodenal ulcer etc.and stomatitis. It is also thought that EP₄ subtype receptor relates tohair growth function. Therefore, the compounds which can bind on EP₄subtype receptor are expected to be useful for the prevention and/ortreatment of hair-disadvantaged and alopecia. Furthermore, it is alsothought that EP₄ subtype receptor relates to maturation of cervix.Therefore, the compounds which can bind on EP₄ subtype receptor areexpected to be useful for the promoter of maturation of cervix.

Furthermore, the compounds which can bind on EP₄ subtype receptor alsohave an action of accelerating bone formation, so it is expected to beuseful for the prevention and/or treatment of diseases associated withdecrease in bone mass, for example,

-   1) primary osteoporosis (e.g., primary osteoporosis followed by    aging, postmenopausal primary osteoporosis, primary osteoporosis    followed by ovariectomy etc.),-   2) secondary osteoporosis (e.g., glucocorticoid-induced    osteoporosis, hyperthyroidism-induced osteoporosis,    immobilization-induced osteoporosis, heparin-induced osteoporosis,    immunosuppressive-induced osteoporosis, osteoporosis due to renal    failure, inflammatory osteoporosis, osteoporosis followed by    Cushing's syndrome, rheumatoid osteoporosis etc.),-   3) bone diseases such as bone metastasis of cancer, hypercalcemia,    Paget's disease, bone loss (alveolar bone loss, mandibular bone    loss, childhood idiopathic bone loss etc.), osteonecrosis etc.

Besides treatment of the above diseases, the present invention alsoincludes a pharmaceutical composition for accelerating bone formationafter bone operation (e.g., bone formation after fractures, boneformation after bone grafting, bone formation after operation ofartificial joint, bone formation after spinal fusion and bone formationafter the other operation for bone regeneration etc.), or promotingtreatment thereof, or alternative treatment for bone grafting.

It is also thought that EP₄ subtype receptor relates to induction ofphysiological sleeping and suppression of blood platelet aggregation, sosuch compounds are expected to be useful for the prevention and/ortreatment of sleep disorder and thrombosis The compound which can bindan EP₄ receptor selectively do not have inducing pain which may becaused by EP₁, uterine relaxation which may be caused by EP₂ and uterinecontraction which may be caused by EP₃, so they are thought to be agentshaving no effect on the above actions.

In the specification of U.S. Pat. No. 4,177,346, it is disclosed thatthe compound of formula (A)

-   -   (wherein Q^(A) is selected from the group consisting of        —COOR^(3A), tetrazol-5-yl and —CONH^(4A);    -   A^(A) is single bond or cis-double bond;    -   B^(A) is single bond or trans-double bond;    -   U^(A) is    -   R^(2A) is selected from the group consisting of α-thienyl,        phenyl, phenoxy, mono-substituted phenyl and mono-substituted        phenoxy, and the substituent is selected from the group        consisting of chloro, fluoro, phenyl, methoxy, trifluoromethyl        and C1-3 alkyl;    -   R^(3A) is selected from the group consisting of hydrogen, C1-5        alkyl, phenyl and p-biphenyl;    -   R^(4A) is selected from the group consisting of —COR and        —SO₂R^(5A);    -   R^(5A) is selected from the group consisting of phenyl and C1-5        alkyl),    -   and a C5 epimer thereof, the salt of alkali metal and alkaline        earth metals and ammounium salt of the compound which have        carboxylate or tetrazol-5-yl.

And in the specification of JP-A-2001-181210, it is disclosed that theselective EP₄ receptor agonist of formula (A) is useful for thetreatment of osteoporosis.

And in the specification of United Kingdom Patent No. 1,553,595, thepyrrolidone derivatives of formula (B)

-   -   (wherein R^(1B) is a straight- or branched-chain, saturated or        unsaturated, aliphatic hydrocarbon radical having up to 10        carbon atoms, or a cycloaliphatic hydrocarbon radical having 3        to 7 carbon atoms, which radicals may be unsubstituted or        substituted by one or more of the following:

-   e) a cycloalkyl group of 3 to 7 carbon atoms,

-   f) a phenyl, thienyl or furyl group which may carry one or two    substituents selected from optionally halogenated alkyl group of 1    to 3 carbon atoms, halogen atoms and alkoxy group of 1 to 4 carbon    atoms,    -   R²B is a straight- or branched-chain, saturated or unsaturated,        aliphatic or cycloaliphatic hydrocarbon radical having up to 6        carbon atoms, or an araliphatic hydrocarbon radical having 7 or        8 carbon atoms, and    -   nB is the integer 2,3 or 4, the definitions of the symbols are        excerpt), and a corresponding acid, a salt, especially the        physiologically acceptable e.g. metal or amine, a salt thereof        is disclosed.

In the specifications of United Kingdom Patent No.1,569,982, and UnitedKingdom Patent No.1,583,163, the compound close to the compound offormula (B) is disclosed.

In the specification of U.S. Pat. No. 4,320,136, the compound of formula(C)

-   -   (wherein A^(C) is CH═CH (cis or trans), C≡C or CH₂CH₂;    -   R^(C) is H, C1-C12 n-alkyl, branched alkyl or cycloalkyl etc.;    -   R^(1C) is H, CH₃ or C₂H₅;    -   R^(2C) is phenyl or mono- or di-substituted phenyl, the        substituent is selected from is selected from the group        consisting of, F, Cl, CH₃, OCH₃, NO₂ or CF₃;        when R^(2C) is phenyl or substituted phenyl,nC is 0-2, the        definitions of the symbols are excerpt) is disclosed.

In the specification of WO00/03980, it is disclosed that the compound offormula (I-1) is useful as EP₄ receptor binding agent.

In the specification of WO01/37877, it is disclosed that the EP₄receptor agonist of formula (I-1) is useful for treatment of diseasesassociated with decrease in bone mass.

It is disclosed that the EP₄ receptor agonist of formulae (A) and (I-1)is useful for treatment of diseases associated with bone, there is ageneral description about topical administration. Therefore it isunproved that topical administration of the EP₄ receptor agonist isuseful for treatment of diseases associated with bone experimentally.

Four PGE₂ subtype receptors possessing a different physical role fromeach other exist, and each subtype is called EP₁, EP₂, EP₃, and EP₄ andhas a different pharmacological action. So the compounds which can bindon EP₄ subtype receptor selectively and binds on the other subtypereceptors weakly may be the drug with less side effect, because theyshow no any other activities. Therefore it is in need of finding thedrug like this.

On the other hand, a lot of compounds which have the EP₄ agonisticactivity are found until now. However, all of them have a prostanoidskeleton, so it is thought that they influence circulatory system (e.g.blood pressure lowered or increasing of the heart rate), or causeside-effect such as diarrhea when they are administered by systemicadministration such as oral administration or intravenous infusion.Therefore, they have significant problem that there is a limitation ofthe dose that can be administered safely.

As a disease associated with EP₄ agonist, a lot of studies of diseasesassociated with decrease in bone mass have been done. It is also thoughtthat systemic administration causes side-effects, so development of thedrug with less side effects is expected. Finding a long-actingpharmaceutical which can be administrated topically is also expected.

DISCLOSURE OF THE INVENTION

The present inventors have studied to find out the compounds which canbind on EP₄ subtype receptor specifically, and which have strongagonistic activity. Finally, the compounds of formulae (I-2) and (I-3)were found out to meet this purpose, and this invention wasaccomplished.

The present inventors found out the compound which binds on both EP₄ andEP₂ subtype receptor. The compound which binds on both EP₄ and EP₂subtype receptor is expected additive or multiplier effect whentreatment of the disease associated with both subtype receptor.

The present inventors also thought that we can create the therapeuticagent (treatment of diseases associated with decrease in bone mass,particularly) with no side-effect in systemic administration if EP₄agonist can be administered topically. We also conceived that we cancreate the therapeutic agent (treatment of diseases associated withdecrease in bone mass, particularly) with no side-effect in systemicadministration and with less frequency of administration if we can findthe EP₄ agonist which can be a sustained release formulation and whichcan be administered topically.

Therefore the present inventors made further investigation to solve theformer purpose to find that the purpose of the present invention can beaccomplished by using a sustained release formulation of the compound offormulae (I-1), (I-2) and (I-3), and completed the present invention.

The compounds of formulae (I-2) and (I-3) is completely novel.

The present invention relates to

-   i) a pharmaceutical composition for topical administration for    prevention and/or treatment of diseases associated with decrease in    bone mass comprising an EP₄ agonist as an active ingredient,-   ii) a sustained release formulation comprising an EP₄ agonist as an    active ingredient,-   iii) a pharmaceutical composition for topical administration for    prevention and/or treatment of diseases associated with decrease in    bone mass comprising a sustained release formulation comprising an    EP₄ agonist as an active ingredient,-   iv) a pharmaceutical composition for prevention and/or treatment of    diseases associated with decrease in bone mass, characterized by    topical administration of the formulation comprising a compound    selected from the group of formula (I-1)    -   wherein R¹⁻¹ is hydroxy, C1-6 alkyloxy, or NR⁶⁻¹R⁷⁻¹, wherein        R⁶⁻¹ and R⁷⁻¹ are each independently, hydrogen atom or C1-4        alkyl,    -   R²⁻¹ is oxo, halogen, or O—COR⁸⁻¹, wherein R⁸⁻¹ is C1-4 alkyl,        phenyl or phenyl(C1-4 alkyl),    -   R³⁻¹ is hydrogen atom or hydroxy,    -   R^(4a-1) and R^(4b-1) are each independently, hydrogen atom or        C1-4 alkyl,    -   R⁵⁻¹ is phenyl substituted by the group listed below:-   (i) 1 to 3 of    -   C1-4 alkyloxy-C1-4 alkyl,    -   C2-4 alkenyloxy-C1-4 alkyl,    -   C2-4 alkynyloxy-C1-4 alkyl,    -   C3-7 cycloalkyloxy-C1-4 alkyl,    -   C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl,    -   phenyloxy-C1-4 alkyl,    -   phenyl-C1-4 alkyloxy-C1-4 alkyl,    -   C1-4 alkylthio-C1-4 alkyl,    -   C2-4 alkenylthio-C1-4 alkyl,    -   C2-4 alkynylthio-C1-4 alkyl,    -   C3-7 cycloalkylthio-C1-4 alkyl,    -   C3-7 cycloalkyl(C1-4 alkylthio)-C1-4 alkyl or    -   phenylthio-C1-4 alkyl or phenyl-C1-4 alkylthio-C1-4 alkyl,-   (ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl,    -   C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy,    -   C1-4 alkyloxy-C1-4 alkyl and hydroxy,    -   C1-4 alkyloxy-C1-4 alkyl and halogen,    -   C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl,    -   C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy,    -   C1-4 alkylthio-C1-4 alkyl and hydroxy or    -   C1-4 alkylthio-C1-4 alkyl and halogen,-   (iii) haloalkyl or hydroxy-C1-4 alkyl, or-   (iv) C1-4 alkyl and hydroxy;    -   is single bond or double bond,    -   wherein when R²⁻¹ is O-COR⁸⁻¹, C8-9 position is double bond,    -   or a non-toxic salt thereof, or a cyclodextrin clathrate thereof        as an active ingredient,-   v) the sustained release formulation comprising a compound selected    from the group of formula (I-1), or a non-toxic salt thereof, or a    cyclodextrin clathrate thereof as an active ingredient,-   vi) a pharmaceutical composition for prevention and/or treatment of    diseases associated with decrease in bone mass, characterized by    topical administration of the formulation comprising a compound    selected from the group of formula (I-2)    -   wherein R¹⁻² is-   (1) —CO—(NH-amino acid residue-CO)_(m-2)—OH,-   (2) —COO—Y²—R⁹⁻²,-   (3) —COO-Z¹⁻²-Z²⁻²-Z³⁻²,    -   wherein Y² is bond or C1-10 alkylene,    -   R⁹⁻² is (1) phenyl or (2) biphenyl optionally substituted by 1-3        C1-10 alkyl, C1-10 alkoxy or halogen atom,    -   Z¹⁻² is-   (1) C1-15 alkylene,-   (2) C2-15 alkenylene or-   (3) C2-15 alkynylene,    -   Z²⁻² is-   (1) —CO—,-   (2) —OCO—,-   (3) —COO—,-   (4) —CONR¹¹⁻²—,-   (5) —NR¹²⁻²CO—,-   (6) —O—,-   (7) —S—,-   (8) —SO—,-   (9) —SO₂—,-   (10) —NR¹³⁻²—,-   (11) —NR¹⁴⁻²CONR¹⁵⁻²—,-   (12) —NR¹⁶⁻²COO—,-   (13) —OCONR¹⁷⁻²— or-   (14) —OCOO—,    -   Z³⁻² is-   (1) hydrogen atom,-   (2) C1-15 alkyl,-   (3) C2-15 alkenyl,-   (4) C2-15 alkynyl,-   (5) ring1² or-   (6) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10    alkyl-NR¹⁸⁻²— or ring1²,    -   ring1² is-   (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially    or fully saturated or-   (2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl containing    1 to 4 hetero atom selected from oxygen, nitrogen and sulfur atom(s)    which may be partially or fully saturated,    -   R¹¹⁻², R¹²⁻², R¹³⁻², R¹⁴⁻², R¹⁵⁻², R¹⁶⁻², R¹⁷⁻² and R¹⁸⁻² are        each independently, hydrogen atom or C1-15 alkyl,    -   R¹¹⁻² and Z³⁻² may be taken together with the nitrogen atom to        which they are attached to form 5 to 7 membered saturated        monoheterocyclic ring, and the heterocyclic ring may contain        another one hetero atom selected from oxygen, nitrogen and        sulfur atom,    -   ring1² and saturated monoheterocyclic ring formed by R¹¹⁻², Z³⁻²        and the nitrogen atom to which Z³⁻² is attached may be        substituted by 1-3 group(s) selected from-   (1) C1-15 alkyl,-   (2) C2-15 alkenyl,-   (3) C2-15 alkynyl and-   (4) C1-10 alkyl substituted with C1-10 alkoxy, C1-10 alkylthio or    C1-10 alkyl-NR¹⁹⁻²,    -   R¹⁹⁻² is hydrogen atom or C1-10 alkyl,    -   m-2 is 1 or 2,    -   other symbols are same meaning as definedhereinbefore,    -   or a non-toxic salt thereof, or a cyclodextrin clathrate thereof        as an active ingredient,-   vii) the sustained release formulation comprising a compound    selected from the group of formula (I-2), or a non-toxic salt    thereof, or a cyclodextrin clathrate thereof as an active    ingredient,-   viii) a pharmaceutical composition for prevention and/or treatment    of diseases associated with decrease in bone mass, characterized by    topical administration of the formulation comprising a compound    selected from the group of formula (I-3)    -   wherein        is (1) single bond or (2) double bond,    -   R¹⁹⁻³ and R²⁰⁻³ are each independently, (1) hydrogen atom, (2)        C1-10 alkyl or (3) halogen atom,    -   T³ is (1) oxygen atom or (2) sulfur atom,    -   X³ is (1) —CH₂—, (2) —O— or (3) —S—,    -   A³ is A¹⁻³ or A²⁻³,    -   A¹⁻³is-   (1) C2-8 straight-chain alkylene optionally substituted by 1-2 C1-4    alkyl,-   (2) C2-8 straight-chain alkenylene optionally substituted by 1-2    C1-4 alkyl or-   (3) C2-8 straight-chain alkynylene optionally substituted by 1-2    C1-4 alkyl,    -   A²⁻³ is -G¹⁻³-G²⁻³-G³⁻³,    -   G¹⁻³ is-   (1) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4    alkyl,-   (2) C2-4 straight-chain alkenylene optionally substituted by 1-2    C1-4 alkyl or-   (3) C2-4 straight-chain alkynylene optionally substituted by 1-2    C1-4 alkyl,    -   G²⁻³ is-   (1) —Y³—,-   (2) -(ring1³)-,-   (3) —Y³-(ring1³)-,-   (4) -(ring1³)-Y³— or-   (5) —Y³—(C1-4 alkylene)-(ring1³)-,    -   Y³ is (1) —S—, (2) —SO—, (3) —SO₂—, (4) —O— or (5) —NR¹⁻³—,    -   R¹⁻³ is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl,    -   G³⁻³ is-   (1) bond,-   (2) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4    alkyl,-   (3) C2-4 straight-chain alkenylene optionally substituted by 1-2    C1-4 alkyl or-   (4) C2-4 straight-chain alkynylene optionally substituted by 1-2    C1-4 alkyl,    -   D³ is D¹⁻³ or D²⁻³,    -   D¹⁻³ is-   (1) —COOH,-   (2) —COOR²⁻³,-   (3) tetrazol-5-yl or-   f(4) CONR³⁻³SO₂R⁴⁻³,    -   R²⁻³ is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted        by phenyl or (4) biphenyl,    -   R³⁻³ is (1) hydrogen atom or (2) C1-10 alkyl,    -   R⁴⁻³ is (1) C1-10 alkyl or (2) phenyl,    -   D²⁻³ is-   (1) —CH₂OH,-   (2) —CH₂OR⁵⁻³,-   (3) hydroxy,-   (4) —OR⁵⁻³,-   (5) formyl,-   (6) —CONR⁶⁻³R⁷⁻³,-   (7) —CONR⁶⁻³SO₂R⁸⁻³,-   (8) —CO—(NH-amino acid residue-CO)_(m-3)—OH,-   (9) —O—(CO-amino acid residue-NH)_(m-3)—H,-   (10) —COOR⁹⁻³,-   (11) —OCO—R¹⁰⁻³,-   (12) —COO-Z¹⁻³-Z²⁻³-Z³⁻³,    -   R⁵⁻³ is C1-10 alkyl,    -   R⁶⁻³ and R⁷⁻³ are each independently, (1) hydrogen atom or (2)        C1-10 alkyl,    -   R⁸⁻³ is C1-10 alkyl substituted by phenyl,    -   R⁹⁻³ is (1) C1-10 alkyl substituted by biphenyl optionally        substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom        or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or        halogen atom,    -   R¹⁰⁻³ is (1) phenyl or (2) C1-10 alkyl,    -   m-3 is 1 or 2,    -   Z¹⁻³ is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3) C2-15        alkynylene,    -   Z²⁻³ is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR¹¹⁻³—, (5)        —NR¹²⁻³CO—, (6) —O—, (7) —S—, (8) —SO—, (9) —SO₂—, (10)        —NR¹³⁻³—, (11) —NR¹⁴⁻³CONR¹⁵⁻³—, (12) —NR¹⁶⁻³COO—, (13)        —OCONR¹⁷⁻³— or (14) —OCOO—,    -   Z³⁻³ is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15        alkenyl, (4) C2-15 alkynyl, (5) ring2³ or (6) C1-10 alkyl        substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10        alkyl-NR¹⁸⁻³— or ring2³,    -   R¹¹⁻³, R¹²⁻³, R¹³⁻³, R¹⁴⁻³, R¹⁵⁻³, R¹⁶⁻³, R¹⁷⁻³ and R¹⁸⁻³ are        each independently, (1) hydrogen atom or (2) C1-15 alkyl,    -   R¹¹⁻³ and Z³⁻³ may be taken together with the nitrogen atom to        which they are attached to form 5 to 7 membered saturated        monoheterocyclic ring, and the heterocyclic ring may contain        other one hetero atom selected from oxygen, nitrogen and sulfur        atom,    -   E³ is E¹⁻³ or E²⁻³,    -   E¹⁻³ is-   (1) C3-7 cycloalkyl or-   (2) ring3³,    -   E²⁻³ is-   (1) C3-7 cycloalkyl,-   (2) ring4³ or-   (3) ring5³,    -   ring1³ and ring5³are optionally substituted by 1-3 R²¹⁻³ and/or        R²²⁻³,    -   ring3³ is optionally substituted by 1-2 R²¹⁻³,    -   C3-7 cycloalkyl represented by E²⁻³ is substituted by one of        R²¹⁻³ or R²²⁻³, and optionally substituted by another 1-2 R²¹⁻³        and/or R²²⁻³,    -   ring4³ is substituted by one of R²²⁻³, optionally substituted by        another 1-2 R²¹⁻³ and/or R²²⁻³, and    -   optionally substituted by heterocyclic ring formed by R¹¹⁻³,        Z³⁻³ and the nitrogen to which Z³⁻³ is attached or ring2³ may be        substituted by R²³⁻³,    -   R²¹⁻³ is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen        atom, (4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen        atom(s) or (6) phenyl,    -   R²²⁻³ is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3) C1-10        alkylthio, (4) hydroxy, (5) —NR²⁴⁻³R²⁵⁻³, (6) C1-10 alkyl        substituted by C1-10 alkoxy, (7) C1-10 alkyl substituted by        C1-10 alkoxy substituted by 1-3 halogen atom(s), (8) C1-10 alkyl        substituted by —NR²⁴⁻³R²⁵⁻³, (9) ring6³, (10) —O-ring7³, (11)        C1-10 alkyl substituted by ring7³, (12) C2-10 alkenyl        substituted by ring7³, (13) C2-10 alkynyl substituted by        ring7³, (14) C1-10 alkoxy substituted by ring7³, (15) C1-10        alkyl substituted by —O-ring7³, (16) —COOR²⁶⁻³ or (17) C1-10        alkoxy substituted by 1-3 halogen atom(s)(s),    -   R²⁴⁻³, R²⁵⁻³ and R²⁶⁻³ are each independently, (1) hydrogen atom        or (2) C1-10 alkyl,    -   R²³⁻³ is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 alkynyl        or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio        or C1-10 alkyl-NR²⁷⁻³—,    -   R²⁷⁻³ is (1) hydrogen atom or (2) C1-10 alkyl,    -   ring1³, ring2³, ring5³, ring6³ and ring7³ are-   (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially    or fully saturated or-   (2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl containing    1 to 4 hetero atom selected from oxygen, nitrogen and sulfur atom(s)    which may be partially or fully saturated,    -   ring3³ and ring4³ are (1) thienyl, (2) phenyl or (3) furyl,    -   ring6³ and ring7³ may be substituted by 1-3 R²⁸⁻³,    -   R²⁸⁻³ is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10        alkynyl, (4) C1-10 alkoxy, (5) C1-10 alkyl substituted by C1-10        alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl        substituted by 1-3 halogen atom(s) or (9) C1-10 alkyl        substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s),        and    -   wherein-   (1) when T³ is oxygen atom, X³ is CH₂—, A³ is A¹⁻³, and D³ is D¹⁻³,    E³ is E²⁻³,-   (2) ring5³ is not C3-7 cycloalkyl, phenyl, thienyl nor furyl,-   (3) ring6³ is phenyl, then phenyl have at least one R²⁸⁻³,    -   or a non-toxic salt thereof, or a cyclodextrin clathrate thereof        as an active ingredient,-   ix) the sustained release formulation comprising a compound selected    from the group of formula (I-3), or a non-toxic salt thereof, or a    cyclodextrin clathrate thereof as an active ingredient,-   x) a prostaglandin derivative of formula (I-2)    -   wherein all symbols have the same meaning as defined in vi),    -   or a non-toxic salt thereof, or a cyclodextrin clathrate        thereof,-   xi) a process for the preparation of a prostaglandin derivative of    formula (I-2), or a non-toxic salt thereof, or a cyclodextrin    clathrate thereof,-   xii) a pharmaceutical composition comprising of a prostaglandin    derivative of formula (I-2), or a non-toxic salt thereof, or a    cyclodextrin clathrate thereof as an active ingredient,-   xiii) a compound selected from the group of formula (I-3)    -   wherein all symbols have the same meaning as defined in viii),    -   or a non-toxic salt thereof, or a cyclodextrin clathrate thereof-   xiv) a process for the preparation of an 8-azaprostaglandin    derivative of formula (I-3), or a non-toxic salt thereof, or a    cyclodextrin clathrate thereof,-   xv) a pharmaceutical composition comprising of an 8-azaprostaglandin    derivative of formula (I-3), or a non-toxic salt thereof, or a    cyclodextrin clathrate thereof as an active ingredient,-   xvi) a pharmaceutical composition for prevention and/or treatment of    diseases associated with decrease in bone mass, characterized by    topical administration of the formulation comprising a compound    selected from the group consisting of-   (1)    (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (2)    (15α,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (3)    (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (4)    (15α,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (5)    (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (6)    (15α,13E)-9-oxo-15-hydroxy-16-(4-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (7)    (15α,13E)-9-oxo-15-hydroxy-16-(2-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (8)    (15α,13E)-9-oxo-15-hydroxy-16-(2-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (9)    (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (10)    (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (11)    (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (12)    (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (13)    (15α,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (14)    (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (15)    (15α,13E)-9-oxo-15-hydroxy-16-(3-ethoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (16)    (15α,13E)-9-oxo-15-hydroxy-16-(3-isopropyloxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (17)    (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (18)    (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (19)    (15α,13E)-9-oxo-15-hydroxy-16-(3,5-dimethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic    acid,-   (20)    (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (21)    (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (22)    (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (23)    (15α,5Z,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic    acid,-   (24)    (15α)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprostanoic    acid, and-   (25)    (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoic    acid 3-phenylphenyl ester,    -   or a non-toxic salt thereof, or a cyclodextrin clathrate thereof        as an active ingredient,    -   or the sustained release formulation comprising a compound        selected from the former group, or a non-toxic salt thereof, or        a cyclodextrin clathrate thereof as an active ingredient,    -   or a compound selected from the former group, or a non-toxic        salt thereof, or a cyclodextrin clathrate thereof, and a process        for the preparation thereof and a pharmaceutical composition        comprising thereof as an active ingredient.

In the present invention, C1-4 alkyl means methyl, ethyl, propyl, butyland the isomers thereof.

In the present invention, C1-10 alkyl means methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the isomersthereof.

In the present invention, C1-15 alkyl means methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,tridecyl, tetradecyl, pentadecyl and the isomers thereof.

In the present invention, C2-10 alkenyl means ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl and theisomers thereof.

In the present invention, C2-15 alkenyl means ethenyl, propenyl,butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl,undecenyl, dodecenyl, tetradecenyl, pentadecenyl and the isomersthereof.

In the present invention, C2-10 alkynyl means ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and theisomers thereof.

In the present invention, C2-15 alkynyl means ethynyl, propynyl,butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl,undecynyl, dodecynyl, tridecynyl, tetradecynyl, pentadecynyl and theisomers thereof.

In the present invention, straight-chain C1-4 alkylene means methylene,ethylene, trimethylene and tetramethylene.

In the present invention, straight-chain C2-8 alkylene means methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene and octamethylene.

In the present invention, C1-4 alkylene means methylene, ethylene,trimethylene, tetramethylene and the isomers thereof.

In the present invention, C1-10 alkylene means methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene, nonamethylene, decamethylene and theisomers thereof.

In the present invention, C1-15 alkylene means methylene, ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene, nonamethylene, decamethylene,undecamethylene, dodecamethylene, tridecamethylene, tetradecamethylene,pentadecamethylene and the isomers thereof.

In the present invention, straight-chain C2-4 alkenylene meansethenylene, propenylene, butenylene and the isomers thereof.

In the present invention, straight-chain C2-8 alkenylene means C2-8alkenylene which has 1 to 2 double bond(s). It means ethenylene,propenylene, butenylene, pentenylene, hexenylene, heptenylene,octenylene, pentadienylene, hexadienylene, heptadienylene andoctadienylene.

In the present invention, C2-15 alkenylene means ethenylene,propenylene, butenylene, pentenylene, hexenylene, heptenylene,octenylene, nonenylene, decenylene, undecenylene, dodecenylene,tridecenylene, tetradecenylene, pentadecenylene and the isomers thereof.

In the present invention, straight-chain C2-4 alkynylene meansethynylene, propynylene, butynylene.

In the present invention, straight-chain C2-8 alkynylene means C2-8alkenylene which has 1 to 2 triple bond(s). It means ethynylene,propynylene, butynylene, butadiynylene, pentynylene, pentadiynylene,hexynylene, hexadiynylene, heptynylene, heptadiynylene, octynylene,octadiynylene.

In the present invention, C2-15 alkynylene means ethynylene,propynylene, butynylene, pentynylene, hexynylene, heptynylene,octynylene, nonynylene, decynylene, undecynylene, dodecynylene,tridecynylene, tetradecynylene, pentadecynylene and the isomers thereof.

In the present invention, C1-10 alkoxy means methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy andthe isomers thereof In the present invention, C1-10 alkylthio meansmethylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio,heptylthio, octylthio, nonylthio, decylthio and the isomers thereof.

In the present invention, halogen atom means chloride, bromide, fluorideand iodide atom.

In the present invention, biphenyl means 2-phenylphenyl, 3-phenylphenylor 4-phenylphenyl.

In the present invention, C2-10 acyl means ethanoyl, propanoyl,butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyland the isomers thereof.

In the present invention, phenylene means benzene ring which has twoconnectable bonds, i.e.,

Any position can be substituted, and 1,4- or 1,3-disubstituted one ispreferable.

In the present invention, thienylene means thiophene ring which has twoconnectable bonds, i.e.,

Any position can be substituted, and 2,5-disubstituted one ispreferable.

In the present invention, furylene means furan ring which has twoconnectable bonds, i.e.,

Any position can be substituted, and 2,5-disubstituted one ispreferable.

In the present invention, thiazolylene means thiazole ring which has twoconnectable bonds, i.e.,

Any position can be substituted, and 2,5-disubstituted one ispreferable.

In the present invention, oxazolylene means oxazole ring which has twoconnectable bonds, i.e.,

Any position can be substituted, and 2,5-disubstituted one ispreferable.

In the present invention, C3-5cycloalkylene means cyclopropyl,cyclobutyl or cyclopenthyl which have two connectable bonds, i.e.,

Any position can be substituted, and 1,1-disubstituted one ispreferable.

In the present invention, amino acid residue means the amino acidresidue of natural amino acid or abnormal amino acid. Natural aminoacids or abnormal amino acid include, for example, glycine, alanine,valine, leucine, isoleucine, serine, threonine, cystein, methionine,proline, asparagine, glutamine, phenylalanine, tyrosine, tryptophan,aspartic acid, glutamic acid, lysine, arginine, histidine, β-alanine,cystathionine, cystine, homoserine, isoleucine, lanthionine, norleucine,norvaline, ornithine, sarcosine, thyronine.

When the amino acid residue has other amino groups, the amino acid withprotecting group is included the former amino acid residue.

A protecting group of amino group includes, for example,benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl,9-fluorenylmethoxycarbonyl.

In the present invention, 5 to 7 membered saturated mono-heterocyclicring means 5 to 7 membered saturated mono-heterocyclic ring which maycontains another one hetero atom selected from oxygen, nitrogen andsulfur atom. It includes, for example, pyrrolidine, imidazolidine,pyrazolidine, piperidine, piperazine, perhydropyridazine,perhydroazepine, perhydrodiazepine, tetrahydrooxazole (oxazolidine),tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine),tetrahydroisothiazole (isothiazolidine), tetrahydrooxazine,perhydrooxazepine, tetrahydrothiazine, perhydrothiazepine, morpholine,thiomorpholine ring.

In the present invention, C3-15 mono-, bi- or tri-carbocyclic ring whichmay be partially or fully saturated also includes spirocarbocyclic ringand bridged carbocyclic ring. It includes, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,cyclononane, cyclodecane, cycloundecane, cyclododecane, cyclotridecane,cyclotetradecane, cyclopentadecane, cyclopropene, cyclobutene,cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene,cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene,perhydropentalene, azulene, perhydroazulene, indene, perhydroindene,indane, naphthalene, dihydronaphthalene, tetrahydronaphthalene,perhydronaphthalene, heptalene, perhydroheptalene, biphenylene,as-indacene, s-indacene, acenaphthylene, acenaphthene, fluorene,phenalene, phenanthrene, anthracene,9,10-dihydroanthracene,spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]hept-2-ene, bicyclo[3.1.1]heptane,bicyclo[3.1.1]hept-2-ene, bicyclo[3.3.1]-2-heptene,bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, adamantane, noradamantaneetc.

In the present invention, among the 3 to 15 membered mono-, bi- ortri-heterocyclic aryl which may be partially or fully saturatedcontaining 1 to 4 hetero atom(s) selected from oxygen, nitrogen andsulfur atom(s), 3 to 15 membered mono-, bi- or tri-heterocyclic arylcontaining 1 to 4 hetero atom(s) selected from oxygen, nitrogen andsulfur atom(s) includes, for example, pyrrole, imidazole, triazole,tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine,azepine, diazepine, furan, pyran, oxepine, thiophene, thiopyran,thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan,oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole,thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole,indolizine, benzofuran, isobenzofuran, benzothiophene,isobenzothiophene, dithianaphthalene, indazole, quinoline, isoquinoline,quinolizine, purine, phthalazine, pteridine, naphthyridine, quinoxaline,quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole,chromene, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiepine,benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine,benzofurazan, benzothiadiazole, benzotriazole, carbazole,beta-carboline, acridine, phenazine, dibenzofuran, xanthene,dibenzothiophene, phenothiazine, phenoxazine, phenoxathiin, thianthrene,phenanthridine, phenanthroline, perimidine ring etc.

The 3 to 15 membered mono-, bi- or tri-heterocyclic aryl which may bepartially or fully saturated containing 1 to 4 hetero atom(s) selectedfrom oxygen, nitrogen and sulfur atom(s) includes aziridine, azetidine,pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline,triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine,dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine,tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine,perhydropyrimidine, dihydropyridazine, tetrahydropyridazine,perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine,dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, oxirane,oxetane, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran,dihydrooxepine, tetrahydrooxepine, perhydrooxepine, thiirane, thietane,dihydrothiophene, tetrahydrothiophene, dihydrothiopyran,tetrahydrothiopyran, dihydrothiepine, tetrahydrothiepine,perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine),dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole,tetrahydrothiazole (thiazolidine), dihydroisothiazole,tetrahydroisothiazole (isothiazolidine), dihydrofurazan,tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole(oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine,tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine,perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine,perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole(thiadiazolidine), dihydrothiazine, tetrahydrothiazine,dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine,tetrahydrothiazepine, perhydrothiazepine, dihydrothiadiazepine,tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine,thiomorpholine, oxathiane, indoline, isoindoline, dihydrobenzofuran,perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran,dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxathiane,dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole,dihydrobenzazepine, tetrahydrobenzazepine, dihydrobenzodiazepine,tetrahydrobenzodiazepine, benzodioxepane, dihydrobenzoxazepine,tetrahydrobenzoxazepine, dihydrocarbazole, tetrahydrocarbazole,perhydrocarbazole, dihydroacridine, tetrahydroacridine,perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene,tetrahydrodibenzofuran, tetrahydrodibenzothiophene,perhydrodibenzofuran, perhydrodibenzothiophene, dioxolane, dioxane,dithiolane, dithiane, dioxaindan, benzodioxane, chroman,benzodithiolane, benzodithiane, 8-aza-1,4-jioxaspiro[4.5]decane,3-azaspiro[5.5]undecane, 1,3,8-triazaspiro[4.5]decane ring

In the present invention, C1-6 alkyloxy means methoxy, ethoxy, propoxy,butoxy, pentyloxy, hexyloxy and the isomers thereof.

In the present invention, C1-4 alkyloxy means methoxy, ethoxy, propoxy,butoxy and the isomers thereof.

In the present invention, C1-4 alkylthio means methylthio, ethylthio,propylthio, butylthio and the isomers thereof.

In the present invention, C2-4 alkenyloxy means ethenyloxy, propenyloxy,butenyloxy and the isomers thereof.

In the present invention, C2-4 alkenylthio means ethenylthio,propenylthio, butenylthio and the isomers thereof.

In the present invention, C2-4 alkynyloxy means ethynyloxy, propynyloxy,butynyloxy and the isomers thereof.

In the present invention, C2-4 alkynylthio means ethynylthio,propynylthio, butynylthio and the isomers thereof.

In the present invention, C3-7 cycloalkyl means cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the isomers thereof.

In the present invention, C3-7 cycloalkyloxy means cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and theisomers thereof.

In the present invention, C3-7 cycloalkylthio means cyclopropylthio,cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio and theisomers thereof.

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio,alkylene alkenylene and alkynylene group means straight-chain orbranched-chain ones. In addition, isomers on double bond, ring, fusedring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetriccarbon atom(s) (R-, S-, α-, β-isomer, enantiomer, diastereomer),optically active isomers (D-, L-, d-, 1-isomer), polar compoundsgenerated by chromatographic separation (more polar compound, less polarcompound), equilibrium compounds, mixtures thereof at voluntary ratiosand racemic mixtures are also included in the present invention.

In the present invention, unless otherwise specified, the symbol

means that the substituent attached thereto is behind the sheet (i.e.,α-configuration), the symbol

means that the substituent attached thereto is in front of the sheet(i.e., β-configuration), the symbol

means α-configuration, β-configuration or a mixture of α-configurationand β-configuration, and the symbol

means that there is a mixture of α-configuration and β-configuration aswould be clear to the person skilled in the art.

The compound of the present invention may be converted into thecorresponding non-toxic salt by conventional methods.

Non-toxic salts of the compounds of the present invention include allpharmaceutically acceptable salts, and water-soluble salts arepreferred.

Non-toxic salts of the compounds of the present invention, for example,include: salts of alkali metals (e.g. potassium, sodium, lithium, etc.),salts of alkaline earth metals (e.g. calcium, magnesium, etc.), ammoniumsalts (e.g. tetramethylammonium salt, tetrabutylammonium salt, etc.),salts of organic amines (e.g. triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)methylamine,lysine, arginine, N-methyl-D-glucamine, etc.) and acid addition salts(salts of inorganic acids (e.g. hydrochloride, hydrobromide,hydroiodide, sulfate, phosphate, nitrate, etc.), salts of organic acids(e.g. acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate,maleate, benzoate, citrate, methanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate,etc.), etc.).

Non-toxic salts of the compounds of the present invention includesolvates thereof or solvates of the salts of alkali metals, salts ofalkaline earth metals, ammonium salts, salts of organic amines and acidaddition salts of the compounds of the present invention.

Non-toxic and water-soluble solvates are preferred. Solvates of thecompounds of the present invention, for example, include: hydrates,solvates of the alcohols (ethanol etc.), etc.

The compounds of the present invention may be converted into thecorresponding cyclodextrin clathrates by the method described in thespecification of JP-B-50-3362, 52-31404 or 61-52146 using α-, β- orγ-cyclodextrin or a mixture thereof. Converting into the correspondingcyclodextrin clathrates serves to increase the stability and solubilityin water of the compounds, and therefore it is useful in the use forpharmaceuticals.

It is enough to use the compound of the present invention as the EP₄agonist if it has EP₄ agonistic activity. Both a selective EP₄ agonistand a non-selective EP₄ agonist can be used.

Furthermore, the EP₄ agonists of the present invention include the oneswhich will be found newly in future as well as known ones at present.

For example, the EP₄ agonists known at present are prostaglandin E₁(PGE₁), prostaglandin E₂ (PGE₂), 13,14-dihydroprostaglandin E₁, thecompound described in WO00/54808, the compound described in WO01/37877,the compound described in JP-A-2001-181210, the compounds of formulae(I-1), (I-2) and (I-3) described in WO00/03980. Prostaglandin E₂, thecompounds of formulae (I-1), (I-2) and (I-3) is more preferable.

Among the compounds of formula (I-3) of the present invention, A³ ispreferably A¹⁻³ or A²⁻³. More preferably, A³ is A²⁻³.

Among the compounds of formula (I-3) of the present invention, G¹⁻³ ispreferably (1) C1-4 straight-chain alkylene optionally substituted by1-2 C1-4 alkyl, or (2) C2-4 straight-chain alkenylene optionallysubstituted by 1-2 C1-4 alkyl. 1) C1-4 straight-chain alkyleneoptionally substituted by 1-2 C1-4 alkyl is more preferable.

Among the compounds of formula (I-3) of the present invention, G²⁻³ ispreferably (1) —Y³—, (2) -(ring1³)-, or (3) —Y³-(ring1³)-. 1) —Y³— ismore preferable.

Among the compounds of formula (I-3) of the present invention, Y³ ispreferably —S— or —O—. —S— is more preferable.

Among the compounds of formula (I-3) of the present invention, G³⁻³ ispreferably (1) bond, (2) C1-4 straight-chain alkylene optionallysubstituted by 1-2 C1-4 alkyl, or (3) C2-4 straight-chain alkenyleneoptionally substituted by 1-2 C1-4 alkyl. (2) C1-4 straight-chainalkylene optionally substituted by 1-2 C1-4 alkyl is more preferable.

Among the compounds of formula (I-3), T³ is preferably oxygen atom orsulfur atom. Oxygen atom is more preferable.

Among the compounds of formula (I-3), X³ is preferably —CH₂—, —O— or—S—. —CH₂— is more preferable.

Among the compounds of formula (I-3), D³ is preferably —COOH, —COOR²⁻³,—COOR⁹⁻³—, COO-Z¹⁻³-Z²⁻³-Z³⁻³, tetrazol-5-yl,

COOH, —COOR²⁻³, —COOR⁹⁻³— or COO-Z¹⁻³-Z²⁻³-Z³⁻³ is more preferable.—COOH or COO-Z¹⁻³-Z²⁻³-Z³⁻³ is most preferable.

Among the compounds of formula (I-3), R¹⁹⁻³ and R²⁰⁻³ are preferablyhydrogen atom.

Among the compounds of formula (I-3), E³ is preferably ring3³, ring4³ orring5³.

Among the compounds of formula (I-3), ring3³ is preferably phenyl.

Among the compounds of formula (I-3), ring4³ is preferably phenyl.

Among the compounds of formula (I-3), ring5³ is preferably C5-10 mono-or bi-carbocyclic aryl which may be partially or fully saturated, or 5to 10 membered mono- or bi-heterocyclic aryl containing 1 to 2 heteroatom selected from oxygen, nitrogen and sulfur atom(s) which may bepartially or fully saturated. The 5 to 10 membered mono- orbi-heterocyclic aryl containing 1 to 2 hetero atom selected from oxygen,nitrogen and sulfur atom(s) which may be partially or fully saturated ispreferably furan, thiophene, oxazole, thiazole, imidazole, pyridine,pyrimidine, benzofuran, indole, benzothiazole.

Among the compounds of formula (I-3), the hydroxy of 15-position ispreferably α-configuration.

Among the compounds of formula (I-3), C13-14 is preferably double bond.

Among the compounds of formula (I-3), Z¹⁻³ is preferably C1-15 alkylene.C1-8 alkylene is more preferable. C1-4 alkylene is most preferable.

Among the compounds of formula (I-3), Z²⁻³ is preferably —CO—, —OCO—,—COO—, —CONR¹¹⁻³—, —OCONR¹⁷⁻³— or —OCOO—. —OCO—, —OCONR¹⁷⁻³—, —OCOO— ismore preferable.

Among the compounds of formula (I-3), Z³⁻³ is preferably C1-15 alkyl orC1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10alkyl-NR¹³⁻³— or ring2³. C4-12 alkyl is more preferable.

Among the compounds of formula (I-2), R¹⁻² is preferably —COO—Y²—R⁹⁻² or—COO-Z¹⁻²-Z²⁻²-Z³⁻². COO-Z¹⁻²-Z²⁻²-Z³⁻² is more preferable.

Among the compounds of formula (I-2), Z¹⁻² is preferably C1-15 alkylene.C1-8 alkylene is more preferable. C1-4 alkylene is most preferable.

Among the compounds of formula (I-2), Z²⁻² is preferably —CO—, —OCO—,—COO—, —CONR¹¹⁻²—, —OCONR¹⁷⁻²— or —OCOO—. —OCO—, —CONR¹⁷⁻²— or —OCOO— ismore preferable.

Among the compounds of formula (I-2), Z³⁻² is preferably C1-15 alkyl,C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10alkyl-NR¹⁸⁻²— or ring1². C4-12 alkyl is more preferable.

Among the compounds of formula (I-3), preferable compounds are thecompound of formula (I-3-A-1)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-3-A-2)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-3-A-3)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-3-A-4)

(wherein all symbols are the same meanings as defined hereinbefore), andthe compound of formula (I-3-A-5)

(wherein all symbols are the same meanings as defined hereinbefore).

Among the compounds of formula (I-2), preferable compounds are thecompound of formula (I-2-A-1)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-2-A-2)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-2-A-3)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-2-A-4)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-2-A-5)

(wherein all symbols are the same meanings as defined hereinbefore), andthe compound of formula (I-2-A-6)

(wherein all symbols are the same meanings as defined hereinbefore).

Among the compounds of formula (I-1), preferable compounds are thecompound of formula (I-1-A-1)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-1-A-2)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-1-A-3)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-1-A-4)

(wherein all symbols are the same meanings as defined hereinbefore), thecompound of formula (I-1-A-5)

(wherein all symbols are the same meanings as defined hereinbefore), andthe compound of formula (I-1-A-6)

(wherein all symbols are the same meanings as defined hereinbefore).

Specifically, the compounds of the present invention are the compoundsshown in the following tables 1 to 120, the compounds described in theExamples and non-toxic salts thereof. TABLE 1 (I-3-A-1-1)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 2 (I-3-A-1-2)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 3 (I-3-A-1-3)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 4 (I-3-A-1-4)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 5 (I-3-A-1-5)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 6 (I-3-A-1-6)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 7 (I-3-A-1-7)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 8 (I-3-A-1-8)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 9 (I-3-A-1-9)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 10 (I-3-A-1-10)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 11 (I-3-A-2-1)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 12 (I-3-A-2-2)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 13 (I-3-A-2-3)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 14 (I-3-A-2-4)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 15 (I-3-A-2-5)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 16 (I-3-A-2-6)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 17 (I-3-A-2-7)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 18 (I-3-A-2-8)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 19 (I-3-A-2-9)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 20 (I-3-A-2-10)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 21 (I-3-A-3-1)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 22 (I-3-A-3-2)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 23 (I-3-A-3-3)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 24 (I-3-A-3-4)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 25 (I-3-A-3-5)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 26 (I-3-A-3-6)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 27 (I-3-A-3-7)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 28 (I-3-A-3-8)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 29 (I-3-A-3-9)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 30 (I-3-A-3-10)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 31 (I-3-A-4-1)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

18

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 32 (I-3-A-4-2)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

18

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 33 (I-3-A-4-3)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

18

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 34 (I-3-A-4-4)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

18

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 35 (I-3-A-4-5)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

18

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 36 (I-3-A-4-6)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 37 (I-3-A-4-7)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 38 (I-3-A-4-8)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 39 (I-3-A-4-9)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 40 (I-3-A-4-10)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 41 (I-3-A-5-1)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 42 (I-3-A-5-2)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 43 (I-3-A-5-3)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 44 (I-3-A-5-4)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 45 (I-3-A-5-5)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 46 (I-3-A-5-6)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 47 (I-3-A-5-7)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 48 (I-3-A-5-8)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 49 (I-3-A-5-9)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 50 (I-3-A-5-10)

No. D³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 51 (I-3-A-1-11)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 52 (I-3-A-2-11)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 53 (I-3-A-3-11)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 54 (I-3-A-4-11)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 55 (I-3-A-1-12)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 56 (I-3-A-2-12)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 57 (I-3-A-3-12)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 58 (I-3-A-4-12)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 59 (I-3-A-1-13)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 60 (I-3-A-2-13)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 61 (I-3-A-3-13)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 62 (I-3-A-4-13)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 63 (I-3-A-1-14)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 64 (I-3-A-2-14)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 65 (I-3-A-3-14)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 66 (I-3-A-4-14)

No. E³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

TABLE 67 (I-2-A-1-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 68 (I-2-A-1-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 69 (I-2-A-1-3)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 70 (I-2-A-1-4)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 71 (I-2-A-1-5)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 72 (I-2-A-1-6)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 73 (I-2-A-1-7)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 74 (I-2-A-2-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 75 (I-2-A-2-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 76 (I-2-A-2-3)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 77 (I-2-A-2-4)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 78 (I-2-A-2-5)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 79 (I-2-A-2-6)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 80 (I-2-A-2-7)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 81 (I-2-A-3-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 82 (I-2-A-3-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 83 (I-2-A-3-3)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 84 (I-2-A-3-4)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 85 (I-2-A-3-5)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 86 (I-2-A-3-6)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 87 (I-2-A-3-7)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 88 (I-2-A-4-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 89 (I-2-A-4-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 90 (I-2-A-4-3)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 91 (I-2-A-4-4)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 92 (I-2-A-4-5)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 93 (I-2-A-4-6)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 94 (I-2-A-4-7)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 95 (I-2-A-5-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 96 (I-2-A-5-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 97

(I-2-A-5-3) No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 98 (I-2-A-4-4)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 99 (I-2-A-5-5)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 100 (I-2-A-5-6)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 101 (I-2-A-5-7)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 102 (I-2-A-6-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 103 (I-2-A-6-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 104 (I-2-A-6-3)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 105 (I-2-A-6-4)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 106 (I-2-A-6-5)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 107 (I-2-A-6-6)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 108 (I-2-A-6-7)

No. R¹⁻² 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

TABLE 109 (I-1-A-1-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 110 (I-1-A-1-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 111 (I-1-A-2-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 112 (I-1-A-2-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 113 (I-1-A-3-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 114 (I-1-A-3-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 115 (I-1-A-4-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 116 (I-1-A-4-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 117 (I-1-A-5-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 118 (I-1-A-5-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 119 (I-1-A-6-1)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

TABLE 120 (I-1-A-6-2)

No. R⁵⁻¹ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

Among the compounds of formula (I-1), preferable compounds are thecompound in the Example of WO00/03980. More preferable compounds are theCompound (1) to (8) listed below.

Compound (1)

(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acidmethyl ester

Compound (2)

(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methyl-4-hydroxyphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acidmethyl ester

Compound (3)

(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-ethoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid methyl ester

Compound (4)(9β,11α,15α,13E)-9-Fluoro-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid methyl ester

Compound (5) (11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid

Compound (6)

(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methyl-4-hydroxyphenyl)-17,18,19,20-tetranor-5-thiaprost-13 -enoic acid

Compound (7)

(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-ethoxymethylphenyl)-17,18,19,20-tetranor-5thiaprost-13-enoicacid

Compound (8)(9β,11α,15α,13E)-9-Fluoro-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid

Process for Producing Compounds of the Invention:

Among the compounds of the invention, those of formula (I-1) can beproduced according to the methods described in WO00/03980.

Among the compounds of the invention, those of formula (1-3) can beproduced according to the methods mentioned below or according to themethods described in the Examples mentioned below.

-   1) Among the compounds of formula (I-3), those in which T³ is oxygen    and the 13-14 position is a double bond, or that is, those of    formula (IA):    -   wherein all symbols have the same meanings as defined above, can        be produced according to the methods mentioned below.

The compounds of formula (IA) can be produced by reducing a compound offormula (II):

-   -   wherein A^(3′), D^(3′) and E^(3′) have the same meanings as A³,        D³ and E³, respectively, but the hydroxyl, the amino, the        carboxyl or the formyl in the group represented by A^(3′),        D^(3′) and E^(3′) may be protected, if necessary; and the other        symbols have the same meanings as defined above,    -   and then optionally removing the protective group from the        resulting product.

The reaction for reduction is known, and it may be effected, forexample, by processing the compound in an organic solvent (e.g.,tetrahydrofuran, dimethoxyethane, toluene, methylene chloride, diethylether, dioxane) in the presence of a reducing agent (e.g.,borohydride-tetrahydrofuran complex, borohydride-dimethyl sulfidecomplex, diborane) and an asymmetric inducer (e.g.,(R)-2-methyl-CBS-oxazaborolysine, (S)-2-methyl-CBS-oxazaborolysine) at-20 to 50° C.

The removal of the protective group may be effected according to themethods mentioned below.

The reaction for removing the protective group for carboxyl, hydroxyl,amino or formyl is well known, including, for example, the following:

-   (1) alkali hydrolysis,-   (2) deprotection under acidic condition,-   (3) deprotection through hydrogenolysis,-   (4) silyl deprotection,-   (5) deprotection with metal,-   (6) deprotection with organic metal.

These methods are described concretely.

-   (1) The deprotection through alkali hydrolysis may be effected, for    example, in an organic solvent (e.g., methanol, tetrahydrofuran,    dioxane) by the use of an alkali metal hydroxide (e.g., sodium    hydroxide, potassium hydroxide, lithium hydroxide), an alkaline    earth metal hydroxide (e.g., barium hydroxide, calcium hydroxide) or    a carbonate (e.g., sodium carbonate, potassium carbonate), or an    aqueous solution thereof or their mixture, at 0 to 40° C.-   (2) The deprotection under acidic condition may be effected, for    example, in an organic solvent (e.g., dichloromethane, chloroform,    dioxane, ethyl acetate, anisole) with an organic solvent (e.g.,    acetic acid, trifluoroacetic acid, methanesulfonic acid,    p-toluenesulfonic acid) or an inorganic acid (e.g., hydrochloric    acid, sulfuric acid) or their mixture (hydrogen bromide/acetic    acid), at 0 to 100° C.-   (3) The deprotection through hydrogenolysis may be effected, for    example, in a solvent (e.g., ether-type (e.g., tetrahydrofuran,    dioxane, dimethoxyethane, diethyl ether), alcohol-type (e.g.,    methanol, ethanol), benzene-type (e.g., benzene, toluene),    ketone-type (e.g., acetone, methyl ethyl ketone), nitrile-type    (e.g., acetonitrile), amide-type (e.g., dimethylformamide), water,    ethyl acetate, acetic acid, or mixed solvent of two or more of    these), in the presence of a catalyst (e.g., palladium-carbon,    palladium-black, palladium hydroxide, platinum oxide, Raney nickel),    in a normal-pressure or increased-pressure hydrogen atmosphere or in    the presence of ammonium formate, at 0 to 200° C.-   (4) The silyl deprotection may be effected, for example, in a    water-miscible organic solvent (e.g., tetrahydrofuran, acetonitrile)    by the use of tetrabutylammonium fluoride, at 0 to 40° C.-   (5) The deprotection with metal may be effected, for example, in an    acidic solvent (acetic acid, buffer having pH of from 4.2 to 7.2, or    mixture of their solution with organic solvent such as    tetrahydrofuran) in the presence of zinc powder with or without    ultrasonic waves applied thereto, at 0 to 40° C.-   (6) The deprotection with metal complex may be effected, for    example, in an organic solvent (e.g., dichloromethane,    dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile,    dioxane, ethanol), water or their mixed solvent, in the presence of    a trapping reagent (e.g., tributyltin hydride, triethylsilane,    dimedone, morpholine, diethylamine, pyrrolidine), an organic acid    (e.g., acetic acid, formic acid, 2-ethylhexanoic acid) and/or an    organic acid salt (e.g., sodium 2-ethylhexanoate, potassium    2-ethylhexanoate), in the presence or absence of a phosphine-type    reagent (e.g., triphenyl phosphine), by the use of a metal complex    (tetrakistriphenylphosphine palladium(0),    dichlorobis(triphenylphosphine) palladium(II), palladium(II)    acetate, chlorotris(triphenylphosphine) rhodium(I)), at 0 to 40° C.

Apart from the above, the deprotection may also be effected, forexample, according to the methods described in T. W Greene, ProtectiveGroups in Organic Synthesis, Wiley, New York, 1999.

The carboxyl-protective group includes, for example, methyl, ethyl,allyl, t-butyl, trichloroethyl, benzyl (Bn), and phenacyl.

The hydroxyl-protective group includes, for example, methyl, trityl,methoxymethyl (OM), 1-ethoxyethyl (EE), methoxyethoxyethyl (MEM),2-tetrahydropyranyl (THP), trimethylsilyl (TMS), triethylsilyl (TES),t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), acetyl (Ac),pivaloyl, benzoyl, benzyl (Bn), p-methoxybenzyl, allyloxycarbonyl(Alloc), and 2,2,2-trichloroethoxycarbonyl (Troc).

The amino-protective group includes, for example, benzyloxycarbonyl,t-butoxycarbonyl, allyloxycarbonyl (Alloc), 1-methyl-i-(4-biphenyl)ethoxycarbonyl (Bpoc), trifluoroacetyl,9-fluorenylmethoxycarbonyl, benzyl (Bn), p-methoxybenzyl,benzyloxymethyl (BOM), and 2-(trimethylsilyl)ethoxymethyl (SEM).

The formyl-protective group is, for example, acetal (e.g.,dimethylacetal).

The carboxyl, hydroxyl, amino or formyl-protective may be any othersthan those mentioned above, capable of being readily and selectivelyremoved, and are not specifically defined. For example, those describedin T. W. Greene, Protective Groups in Organic Synthesis, 3rd Ed., Wiley,New York, 1999 may be used.

The intended compounds of the invention may be readily produced throughselective use of the deprotecting reaction, which could be readilyunderstood by anyone skilled in the art.

-   2) Among the compounds of formula (1-3), those in which T³ is oxygen    and the 13-14 position is a single bond, or that is, those of    formula (IB):    -   wherein all symbols have the same meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (IB) can be produced by hydrogenating acompound of formula (III):

-   -   wherein R²⁹⁻³ represents hydrogen, or a hydroxyl-protective        group, and the other symbols have the same meanings as defined        above,    -   and then optionally removing the protective group from the        resulting product.

The reaction for hydrogenation is known, and it may be effected, forexample, by processing the compound in an organic solvent (e.g.,ether-type (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethylether), alcohol-type (e.g., methanol, ethanol), benzene-type (e.g.,benzene, toluene), ketone-type (e.g., acetone, methyl ethyl ketone),nitrile-type (e.g., acetonitrile), amide-type (e.g., dimethylformamide),water, ethyl acetate, acetic acid, or mixed solvent of two or more ofthese), in the presence of a catalyst (e.g., palladium-carbon,palladium-black, palladium hydroxide, platinum oxide, Raney nickel), ina normal-pressure or increased-pressure hydrogen atmosphere or in thepresence of ammonium formate, at 0 to 200° C.

The removal of the protective group may be effected in the same manneras herein.

-   3) Among the compounds of formula (I-3), those in which T³ is    sulfur, or that is, those of formula (IC):    -   wherein all symbols have the same meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (IC) can be produced by thioamidating acompound of formula (IV):

-   -   wherein all symbols have the same meanings as defined above,    -   and then optionally removing the protective group from the        resulting product.

The reaction for thioamidation is known, and it may be effected, forexample, by processing the compound in an organic solvent (e.g.,toluene, diethyl ether, methylene chloride, chloroform, dioxane,tetrahydrofuran) in the presence of a thionating agent (e.g., Rawsonreagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfide),diphosphorus pentoxide) at 0 to 150° C.

The removal of the protective group may be effected in the same manneras herein.

-   4) Among the compounds of formula (I-3), those in which D³ is    —CH₂OH, or that is, those of formula (ID):    -   wherein all symbols have the same meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (ID) can be produced by reducing a compound offormula (V):

-   -   wherein R³⁰⁻³ represents C1-10 alkyl, and the other symbols have        the same meanings as defined above,    -   and then optionally removing the protective group from the        resulting product.

The reaction for reduction is known, and it may be effected, forexample, by processing the compound in an organic solvent (e.g.,tetrahydrofuran, dimethoxyethane, diethyl ether, dimethylformamide,dioxane, methanol, ethanol, isopropanol) or in its aqueous solution, inthe presence of a reducing agent (e.g., sodium borohydride, lithiumborohydride), at 0 to 70° C.

The removal of the protective group may be effected in the same manneras herein.

-   5) Among the compounds of formula (I-3), those in which D³ is    —CONR³⁻³SO₂R⁴⁻³, —CONR⁶⁻³R⁷⁻³, —CONR⁶⁻³SO₂R⁸⁻³, or —CO—(NH-amino    acid residue-CO)_(m-3)—OH, or of formula (IE):    -   wherein D^(3″) represents —CONR³⁻³SO₂R⁴⁻³, —CONR⁶⁻³R⁷⁻³,        —CONR⁶⁻³SO₂R⁸⁻³, or —CO—(NH-amino acid residue-CO)_(m-3)—OH, and        the other symbols have the same meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (IE) can be produced by amidating a compound offormula (VI):

-   -   wherein all symbols have the same meanings as defined above,    -   with a compound of formula (VII-1):        H—NR³⁻³SO₂R⁴⁻³   (VII-1)    -   wherein all symbols have the same meanings as defined above,    -   or a compound of formula (VII-2):        H—NR⁶⁻³R⁷⁻³   (VII-2)    -   wherein all symbols have the same meanings as defined above,    -   or a compound of formula (VII-3):        H—NR⁶⁻³SO₂R⁸⁻³   (VII-3)    -   wherein all symbols have the same meanings as defined above,    -   or a compound of formula (VII-4):        H—(NH-amino acid residue-CO)_(m-3)—OH   (VII-4)    -   wherein all symbols have the same meanings as defined above, but        the amino, the hydroxyl or the carboxyl in the compound of        formula (VII-4) may be protected, if necessary,    -   and then optionally removing the protective group from the        resulting product.

The reaction for amidation is known, for example, including thefollowing:

-   (1) with acid halide,-   (2) with mixed acid halide,-   (3) with condensing agent.

These methods are described concretely.

-   (1) The method with an acid halide comprises, for example, reacting    the carboxylic acid with an acid-halogenating agent (e.g., oxalyl    chloride, thionyl chloride) in an organic solvent (e.g., chloroform,    dichloromethane, diethyl ether, tetrahydrofuran) or in the absence    of a solvent, at −20° C. to a reflux temperature, followed by    reacting the resulting acid halide with the amine in an inert    organic solvent (e.g., chloroform, dichloromethane, diethyl ether,    tetrahydrofuran) in the presence of a base (pyridine, triethylamine,    dimethylaniline, dimethylaminopyridine, diisopropylethylamine), at 0    to 40° C. If necessary, the acid halide may be reacted in an organic    solvent (e.g., dioxane, tetrahydrofuran) by the use of an aqueous    alkali solution (e.g., aqueous sodium bicarbonate, sodium hydroxide    solution) at 0 to 40° C.-   (2) The method with a mixed acid anhydride comprises, for example,    reacting the carboxylic acid with an acid halide (e.g., pivaloyl    chloride, tosyl chloride, mesyl chloride) or an acid derivative    (e.g., ethyl chloroformate, isobutyl chloroformate) in an organic    solvent (e.g., chloroform, dichloromethane, diethyl ether,    tetrahydrofuran) or in no solvent, in the presence of a base (e.g.,    pyridine, triethylamine, dimethylaniline, dimethylaminopyridine,    diisopropylethylamine), at 0 to 40° C, followed by reacting the    resulting mixed acid anhydride with the amine in an organic solvent    (e.g., chloroform, dichloromethane, diethyl ether, tetrahydrofuran)    at 0 to 40° C.-   (3) The method with a condensing agent comprises, for example,    reacting the carboxylic acid with the amine in an organic solvent    (e.g., chloroform, dichloromethane, dimethylformamide, diethyl    ether, tetrahydrofuran) or in no solvent, in the presence or absence    of a base (e.g., pyridine, triethylamine, dimethylaniline,    dimethylaminopyridine) by the use of a condensing agent (e.g.,    1,3-dicyclohexylcarbodiimide (DCC),    1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),    1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,    1-propanephosphonic acid cyclic anhydride (PPA)), and by the use of    or with no use of 1-hydroxybenzotriazole (HOBt) or    1-methanesulfonyloxybenzotriazole, at 0 to 40° C.

Preferably, the reactions (1), (2) and (3) are all effected in an inertgas (e.g., argon, nitrogen) atmosphere with no water.

The removal of the protective group may be effected in the same manneras herein.

-   6) Among the compounds of formula (I-3), those in which D³ is    —O—(CO-amino acid residue-NH)_(m-3)—H or —OCO—R¹⁰⁻³, or that is,    those of formula (IF):    -   wherein D^(3″) represents —O—(CO-amino acid residue-NH)_(m-3)—H        or —OCO—R^(10-3,) and the other symbols have the same meanings        as defined above, can be produced according to the methods        mentioned below.

The compounds of formula (IF) can be produced by esterifying a compoundof formula (VIII):

-   -   wherein R³¹⁻³ represents —OH or —CH₂OH, and the other symbols        have the same meanings as defined above,    -   with a compound of formula (IX-1):        HO—(CO-amino acid residue-NH)_(m-3)—H   (IX-1)    -   wherein all symbols have the same meanings as defined above, but        the amino, the hydroxyl or the carboxyl in the compound of        formula (IX-1) may be protected, if necessary,    -   or a compound of formula (IX-2):        HOOC—R¹⁰⁻³   (IX-2)    -   wherein R¹⁰⁻³ has the same meaning as above,    -   and then optionally removing the protective group from the        resulting product.

The reaction for esterification is known, for example, including thefollowing:

-   (1) with acid halide,-   (2) with mixed acid halide,-   (3) with condensing agent.

These methods are described concretely.

-   (1) The method with an acid halide comprises, for example, reacting    the carboxylic acid with an acid-halogenating agent (e.g., oxalyl    chloride, thionyl chloride) in an organic solvent (e.g., chloroform,    dichloromethane, diethyl ether, tetrahydrofuran) or in the absence    of a solvent, at −20° C. to a reflux temperature, followed by    reacting the resulting acid halide with the alcohol in the presence    of a base (pyridine, triethylamine, dimethylaniline,    dimethylaminopyridine, diisopropylethylamine), in an inert organic    solvent (e.g., chloroform, dichloromethane, diethyl ether,    tetrahydrofuran) at 0 to 40° C. If necessary, the acid halide may be    reacted in an organic solvent (e.g., dioxane, tetrahydrofuran) by    the use of an aqueous alkali solution (e.g., aqueous sodium    bicarbonate, sodium hydroxide solution) at 0 to 40° C.-   (2) The method with a mixed acid anhydride comprises, for example,    reacting the carboxylic acid with an acid halide (e.g., pivaloyl    chloride, tosyl chloride, mesyl chloride) or an acid derivative    (e.g., ethyl chloroformate, isobutyl chloroformate) in an organic    solvent (e.g., chloroform, dichloromethane, diethyl ether,    tetrahydrofuran) or in no solvent, in the presence of a base (e.g.,    pyridine, triethylamine, dimethylaniline, dimethylaminopyridine,    diisopropylethylamine), at 0 to 40° C, followed by reacting the    resulting mixed acid anhydride with the alcohol in an organic    solvent (e.g., chloroform, dichloromethane, diethyl ether,    tetrahydrofuran) at 0 to 40° C.-   (3) The method with a condensing agent comprises, for example,    reacting the carboxylic acid with the amine in an organic solvent    (e.g., chloroform, dichloromethane, dimethylformamide, diethyl    ether, tetrahydrofuran) or in no solvent, in the presence or absence    of a base (e.g., pyridine, triethylamine, dimethylaniline,    dimethylaminopyridine) by the use of a condensing agent (e.g.,    1,3-dicyclohexylcarbodiimide (DCC),    1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),    1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,    1-propanephosphonic acid cyclic anhydride (PPA)), and by the use of    or with no use of 1-hydroxybenzotriazole (HOBt), at 0 to 40° C.

Preferably, the reactions (1), (2) and (3) are all effected in an inertgas (e.g., argon, nitrogen) atmosphere with no water.

The removal of the protective group may be effected in the same manneras herein.

-   7) Among the compounds of formula (I-3), those in which D³ is    formyl, or that is, those of formula (IG):    -   wherein all symbols have the same meanings as defined above, can        be produced according to the methods mentioned below.

The compounds of formula (IG) can be produced by oxidizing a compound offormula (X):

-   -   wherein all symbols have the same meanings as defined above, and        then optionally removing the protective group from the resulting        product.

The reaction for oxidation is known, for example, including thefollowing:

-   (1) Swern oxidation,-   (2) oxidation with Dess-Martin reagent,-   (3) oxidation with TEMPO reagent.

These methods are described concretely.

-   (1) The method of Swern oxidation comprises, for example, reacting    oxalyl chloride with dimethyl sulfoxide in an organic solvent (e.g.,    chloroform, dichloromethane) at −78° C., and then reacting the    resulting solution with the alcohol compound, and further with a    tertiary amine (e.g., triethylamine, N,N-diisopropylethylamine,    N-methylmorpholine, N-ethylpiperidine,    diazabicyclo[5.4.0]undec-7-ene) at −78 to 20° C.-   (2) The method with a Dess-Martin reagent comprises, for example,    processing the compound in an organic solvent (e.g., chloroform,    dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetonitrile,    t-butyl alcohol) in the presence of a Dess-Martin reagent    (1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one), in the    presence or absence of a base (e.g., pyridine) at 0 to 40° C.-   (3) The method with a TEMPO reagent comprises, for example,    processing the compound in an organic solvent (e.g., chloroform,    dichloromethane, tetrahydrofuran, toluene, acetonitrile, ethyl    acetate, water) or in a mixed solvent thereof, in the presence of a    TEMPO reagent (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical)    and a re-oxidizing agent (aqueous hydrogen peroxide, sodium    hypochlorite, 3-chloroperbenzoic acid, iodobenzene diacetate,    potassium peroxymonosulfate (Oxon, trade name)), in the presence or    absence of a quaternary ammonium salt (e.g., tetrabutylammonium    chloride, tetrabutylammonium bromide), in the presence or absence of    an inorganic salt (e.g., sodium bromide, potassium bromide), in the    presence or absence of an inorganic base (e.g., sodium    hydrogencarbonate, sodium acetate), at 20 to 60° C.

The oxidation is not limited to the above, and may be any other capableof readily and selectively oxidizing the alcohol into a ketone. Forexample, herein employable is any of Johns oxidation, oxidation with PCC(pyridinium chlorochromate), oxidation with sulfur trioxide-pyridinecomplex, or those described in Comprehensive Organic Transformations(Richard C. Larock, VCH Publishers, Inc., (1989), pp. 604-614).

The removal of the protective group may be effected in the same manneras herein.

-   8) Among the compounds of formula (I-3), those in which D³ is    —COOR²⁻³, —COOR⁹⁻³or —COO-Z¹⁻³-Z²⁻³-Z³⁻³, or that is, those of    formula (IH):    -   wherein D^(3″″) represents —OOR²⁻³, —COOR⁹⁻³, or        —COO-Z¹⁻³-Z²⁻³-Z³⁻³, and the other symbols have the same        meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (IH) can be produced by esterifying a compoundof formula (VI):

-   -   wherein all symbols have the same meanings as defined above,    -   with a compound of formula (XI-1):        R³¹⁻³—R²⁻³   (XI-1)    -   wherein R³¹⁻³ represents hydroxyl or halogen, and the other        symbols have the same meanings as defined above,    -   or a compound of formula (XI-2):        R³¹⁻³R⁹⁻³   (XI-2)    -   wherein all symbols have the same meanings as defined above,    -   or a compound of formula (X1-3):        R³¹⁻³-Z¹⁻³⁻¹-Z²⁻³⁻¹-Z³⁻³⁻¹   (X-3)    -   wherein Z¹⁻³⁻¹, Z²⁻³⁻¹ and Z³⁻³⁻¹ have the same meanings as        Z¹⁻³, Z²⁻³ and Z³⁻³, respectively, but the hydroxyl, the amino,        the carboxyl or the formyl in the group of Z¹⁻³⁻¹-Z²⁻³⁻¹-Z³⁻³⁻¹        may be optionally protected, if necessary,    -   and then optionally removing the protective group from the        resulting product.

The esterification with the compound of formulae (XI-1), (XI-2) and(XI-3) in which R³¹⁻³ is hydroxyl may be effected in the same manner asabove.

The esterification with the compound of formulae (XI-1), (XI-2) and(X-3) in which R³¹⁻³ is halogen may be effected, for example, in anorganic solvent (e.g., dimethylformamide, tetrahydrofuran, dioxane,diethyl ether, dimethylacetamide), in the presence of a base (e.g.,potassium carbonate, cesium carbonate, sodium carbonate, potassiumhydrogencarbonate, sodium hydrogencarbonate, potassium hydroxide, sodiumhydroxide) at 0 to 150° C.

The removal of the protective group may be effected in the same manneras herein.

-   9) Among the compounds of formula (I-3), those in which the    substituent of E³ is amino can be produced through reduction of    nitro.

The reaction for nitro reduction is known, and it may be effected, forexample through hydrogenolysis and reduction with organic metal.

The reaction for hydrogenolysis is known, and the deprotection throughhydrogenolysis may be effected, for example, in an inert solvent (e.g.,ether-type (e.g., tetrahydrofuran, dioxane, dimethoxyethane, diethylether), alcohol-type (e.g., methanol, ethanol), benzene-type (e.g.,benzene, toluene), ketone-type (e.g., acetone, methyl ethyl ketone),nitrile-type (e.g., acetonitrile), amide-type (e.g., dimethylformamide),water, ethyl acetate, acetic acid, or mixed solvent of two or more ofthese), in the presence of a hydrogenation catalyst (e.g.,palladium-carbon, palladium-black, palladium, palladium hydroxide,platinum dioxide, nickel, Raney nickel, ruthenium chloride), in thepresence or absence of an inorganic acid (e.g., hydrochloric acid,sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid) oran organic acid (e.g., acetic acid, p-toluenesulfonic acid, oxalic acid,trifluoroacetic acid, formic acid), in a normal-pressure orincreased-pressure hydrogen atmosphere or in the presence of ammoniumformate at 0 to 200° C. In place of the acid, if used, its salt may alsobe used.

The reaction for reduction with organic metal is known, and it may beeffected, for example, in a water-miscible solvent (e.g., ethanol,methanol) in the presence or absence of aqueous hydrochloric acidsolution by the use of an organic metal (e.g., zinc, iron, tin, tinchloride, iron chloride) at 50 to 150° C.

-   10) Among the compounds of formula (I-3), those in which T³ is    oxygen and X³ is —CH₂—, or that is, those of formula (IJ):    -   wherein all symbols have the same meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (IJ) can be produced through reductiveamination of a compound of formula (XII):

-   -   wherein all symbols have the same meanings as defined above,    -   with a compound of formula (XIII):        OHC-A^(3″)D^(3′)  (XIII)    -   wherein A^(3″) represents A^(1′-3) or A^(2′-3),    -   A^(1′-3) represents

-   1) linear C1-7 alkylene optionally substituted by one or two C1-4    alkyl(s),

-   2) linear C2-7 alkenylene optionally substituted by one or two C1-4    alkyl(s), or

-   3) linear C2-7 alkynylene optionally substituted by one or two C1-4    alkyl(s),    -   A^(2′-3) represents -G^(1′-3)-G²⁻³-G³⁻³-,    -   G^(1′-3) represents

-   1) a single bond,

-   2) linear C1-3 alkylene optionally substituted by one or two C1-4    alkyl(s),

-   3) linear C2-3 alkenylene optionally substituted by one or two C1-4    alkyl(s), or

-   4) linear C2-3 alkynylene optionally substituted by one or two C1-4    alkyl(s),    -   and the other symbols have the same meanings as defined above,    -   and then optionally removing the protective group from the        resulting product.

The reaction for reductive amination is known, and it may be effected,for example, in an organic solvent (e.g., ethyl acetate, dichloroethane,dichloromethane, dimethylformamide, tetrahydrofuran, acetic acid, ortheir mixture) in the presence of a reducing agent (e.g., sodiumtriacetoxyborohydride, sodium borocyanohydride, sodium borohydride, zincborohydride, diisobutylaluminium hydride) at −15 to 100° C., or in anorganic solvent (e.g., ethyl acetate, dichloroethane, dichloromethane,methanol, ethanol, acetic acid, or their mixture) in the presence of acatalyst (e.g., palladium-carbon, palladium-black, palladium hydroxide,platinum oxide, Raney nickel) in a normal-pressure or increased-pressurehydrogen atmosphere at 0 to 200° C.

The removal of the protective group may be effected in the same manneras herein.

Among the compounds of the invention, those of formula (I-2) can beproduced according to the methods mentioned below or according to themethods described in the Examples mentioned below.

-   1) Among the compounds of formula (I-2), those in which R¹⁻² is    —CO—(NH-amino acid residue-CO)_(m-2)—OH, or that is, those of    formula (IK):    -   wherein R¹⁻²⁻¹ represents —CO—(NH-amino acid        residue-CO)_(m-2)—OH, and the other symbols have the same        meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (IK) can be produced through amidation of acompound of formula (I-1) in which R¹⁻¹ is hydroxy, or that is, acompound of formula (I-1-1):

-   -   wherein all symbols have the same meanings as defined above,    -   with a compound of formula (XIV):        H—(NH-amino acid residue-CO)_(m-2)—OH   (XIV)    -   wherein all symbols have the same meanings as defined above, but        the amino, the hydroxyl or the carboxyl in the compound of        formula (XIV) may be optionally protected, if necessary,    -   and then optionally removing the protective group from the        resulting product.

The amidation and the deprotection may be effected in the same manner asabove.

-   2) Among the compounds of formula (I-2), those in which R¹⁻² is    —COO—Y²—R⁹⁻², or —COO-Z¹⁻²-Z²⁻²-Z²⁻³, or that is, those of formula    (IL):    -   wherein R¹⁻³⁻² represents —COO—Y²—R⁹⁻², or —COO-Z¹⁻²-Z²⁻²-Z²⁻³,        and the other symbols have the same meanings as defined above,    -   can be produced according to the methods mentioned below.

The compounds of formula (IL) can be produced through esterification ofa compound of formula (I-1-1):

-   -   wherein all symbols have the same meanings as defined above,    -   with a compound of formula (XV-1):        R²³⁻²—Y²—R⁹⁻²   (XV-1)    -   wherein R²³-² represents hydroxyl or halogen, and the other        symbols have the same meanings as defined above,    -   or a compound of formula (XV-2):        R²³⁻²-Z¹⁻²⁻¹-Z²⁻²⁻¹-Z³⁻²⁻¹   (XV-2)    -   wherein Z¹⁻²⁻¹, Z²⁻²⁻¹ and Z³⁻²⁻¹ have the same meanings as        Z¹⁻², Z²⁻² and Z³⁻², respectively, but the hydroxyl, the amino,        the carboxyl or the formyl in the group of Z¹⁻²⁻¹-Z²⁻²⁻¹-Z³⁻²⁻¹        may be optionally protected, if necessary,    -   and then optionally removing the protective group from the        resulting product.

The esterification with the compound of formulae (XV-1) and (XV-2) inwhich R²³⁻² is hydroxyl may be effected in the same manner as above.

The esterification with the compound of formulae (XV-1) and (XV-2) inwhich R²³⁻² is halogen may be effected also in the same manner as above.

The deprotection may be effected also in the same manner as above.

The compounds of formulae (II), (VII-1), (VII-2), (VII-3), (IX-1),(IX-2), (XI-1), (XI-2), (XII), (XIII), (XIV), (XV-1) and (XV-2) are perse known, or are readily produced in known methods.

For example, the compounds of formulae (II) and (XII) can be producedaccording to the following reaction processes 1, 2 and 3.

In these reaction processes, Boc represents t-butoxycarbonyl, R³²⁻³represents hydroxyl-protective, Ac represents an acetyl group, R³³⁻³represents halogen, R³⁴⁻³ represents C1-3 alkylene, R³⁵⁻³ representsC1-4 alkylene, R³⁶⁻³ represents an amino-protective group, and the othersymbols have the same meanings as defined above.

In the reaction processes 1, 2 and 3, the starting compounds of formulae(XVI), (XVII), (XXIII), (XXVII), (XXVIII), (XXXII) and (XXXIII) areknown, or are readily produced in known methods.

The reaction product in each reaction stage in this description may bepurified in an ordinary manner, for example, through normal-pressure orreduced-pressure distillation, or through high-performance liquidchromatography, thin-layer chromatography or column chromatography withsilica gel or magnesium silicate, or through washing orrecrystallization. The purification may be effected in every reactionstage or after some reaction stages.

Industrial Applicability

Application to Pharmaceutical Preparations:

The compounds of the invention represented by formulae (I-2) and (I-3)act on PGE receptor EP₄ subtype specifically and strongly and thus areconsidered useful for prevention and/or treatment of immunodiseases(e.g., autoimmune diseases such as amyotrophic lateral sclerosis (ALS),multiple sclerosis, Sjogren's syndrome, chronic rheumatism and systemiclupus erythematosus, rejection after organ implantation) and diseasessuch as asthma, death of neurocyte, arthritis, lung disorder, fibroidlung, pulmonary emphysema, bronchitis, chronic obstructive respiratorydisease, hepatopathy, acute hepatitis, nephritis (acute nephritis,chronic nephritis), renal insufficiency, hypertension, myocardialischemia, systemic inflammatory response syndrome, septicemia,hemophagocytosis syndrome, macrophage activation syndrome, stilldisease, Kawasaki Disease, thermal burn, systemic granuloma, ulcerativecolitis, Crohn disease, hypercytokinemia during dialysis, multiple organdysfunction syndrome and shock. EP₄ receptor also takes part in mucousmembrane protective action and thus is considered useful for preventionand/or treatment of digestive tract ulcer such as gastric ulcer andduodenal ulcer and stomatitis. EP₄ receptor further takes part intrichogenous action and hair growing action and is considered useful forprevention and/or treatment of alopecia. Moreover, EP₄ receptor takespart in maturation of cervical canal and thus is considered useful as acervical canal maturing agent.

Furthermore, the compound bound to EP₄ receptor has an osteogenesisaccelerating action and thus is considered not only useful forprevention and/or treatment of bone diseases in which the amount of boneis decreased, e.g., 1) primary osteoporosis due to, e.g., aging,menopause, overietomy, 2) secondary osteoporosis (e.g.,glucocorticoid-induced osteoporosis, hyperhyroidismic osteoporosis,fixed induced osteoporosis, haparin-induced osteoporosis,immunosuppression-induced osteoporosis, osteoporosis due to renalinsufficiency, inflammatory osteoporosis, osteoporosis due to Cushing'ssyndrome, rheumatic osteoporosis), 3) bone diseases such as transfer ofcancer to bone, hypercalcemia, Behcet's disease, bone deficiency (e.g.,alveolar bone deficiency, mandible deficiency, infantile idiopathic bonedeficiency) and osteonecrosis but also useful as a agent foraccelerating the osteogenesis/treatment after bone surgery (e.g.,fracture, bone graft, artificial arthrogenesis, spinal fusion, otherbone repair) or substitute for bone transfer.

Moreover, EP₄ acts to induce physiologic sleep and inhibit plateletaggregation and the compound bound to EP₄ receptor is considered usefulfor prevention of somnipathy and thrombosis.

The compound selectively bound to EP₄ has neither pain-giving effectpresumably attributed to EP₁ nor uterine contracting effect presumablyattributed to EP₃ and thus is considered to be a pharmaceuticalpreparation having no such effects.

Among the compounds represented by formula (I-3) are those which areconnected to EP₄ receptor as well as EP₂ receptor. The compoundconnected to EP2 receptor is considered useful for prevention and/ortreatment of immunodiseases (e.g., autoimmune diseases such asamyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren'ssyndrome, chronic rheumatism and systemic lupus erythematosus, rejectionafter organ implantation) and diseases such as asthma, death ofneurocyte, premature birth, miscarriage, pars nervosa retinae troublesuch a glaucoma, erectile insufficiency, arthritis, lung disorder,fibroid lung, pulmonary emphysema, bronchitis, chronic obstructiverespiratory disease, hepatopathy, acute hepatitis, shock, nephritis,renal insufficiency, circulatory system disorder (e.g., hypertension,myocardial ischemia, chronic arterial obstruction, vibration disease),systemic inflammatory response syndrome, septicemia, hemophagocytosissyndrome, macrophage activation syndrome, still disease, KawasakiDisease, thermal burn, systemic granuloma, ulcerative colitis, Crohndisease, hypercytokinemia during dialysis, multiple organ dysfunctionsyndrome and bone disease (e.g., fracture, refracture, bone unioninsufficiency, pseudarthrosis, osteomalacia, bone Behcet's disease,spondylism, transfer of cancer to bone, osteroarthritis, destruction ofbone/cartilage due to these analogous diseases). The compound connectedto EP2 receptor is also considered useful as an agent for acceleratingthe osteogenesis/treatment after bone surgery (e.g., fracture, bonegraft, artificial arthrogenesis, spinal fusion, surgery for multiplemyeloma, lung cancer, breast cancer, etc., other bone repair) orsubstitute for bone transfer. This compound is further considered usefulas an agent for accelerating the regeneration of peridontium inperidontium disease.

The compound connected both to EP₄ receptor and EP₂ receptor can beexpected to exert an additive or synergistic effect on diseases relatedto both the receptors.

The compound represented by formula (I-1), (I-2) or (1-3) or nontoxicsalt thereof may be administered in combination with otherpharmaceutical preparations to accomplish the following purposes:

-   1) To compensate for and/or enhance the preventive and/or treatment    effect of the compound to be combined;-   2) To improve the kinetics/absorption of the compound to be combined    and reduce the dose of the compound; and/or-   3) To eliminate the side effect of the compound to be combined The    compound represented by formula (I-1), (I-2) or (I-3) and other    pharmaceutical preparations may be administered in the form of    formulation having these components incorporated in one preparation    or may be administered in separate preparations. In the case where    these pharmaceutical preparations are administered in separate    preparations, they may be administered simultaneously or at    different times. In the latter case, the compound represented by    formula (I-1), (I-2) or (I-3) may be administered before the other    pharmaceutical preparations. Alternatively, the other pharmaceutical    preparations may be administered before the compound represented by    formula (I-1), (I-2) or (I-3). The method for the administration of    these pharmaceutical preparations may be the same or different.

The diseases on which the preventive and/or treatment effect of theaforementioned combined preparations works are not specifically limitedbut may be those for which the preventive and/or treatment effect of thecompound represented by formula (I-1), (I-2) or (I-3) is compensated forand/or enhanced.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) on bone diseases includephosphodiesterases-4 inhibitor, bisphosphonate preparation, vitamin Dpreparation, calcium adjuvant, estrogen preparation, calcitoninpreparation, isoflavone-based preparation, anabolic steroid preparation,vitamin K preparation, cathepsin K inhibitor, prostaglandins, statin,parathyroid hormone, and growth factors.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) on chronic obstructive lungdiseases and/or asthma include phosphodiesterases-4 inhibitor, steroidpreparation, β₂ adrenoreceptor stimulant, leukotriene receptorantagonist, thromboxane synthesis enzyme inhibitor, thromboxane A₂receptor antagonist, mediator liberation inhibitor, antihistamines,xanthine derivatives, anticholinergic preparation, cytokine inhibitor,prostaglandins, metaprotease inhibitor, expectorant, and antibiotic.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) on arthritis or chronicarticular rheumatism include metaprotease inhibitor, immunosuppressant,nonsteroid-based antiphlogistic (NSAID), steroid preparation, andphosphodiesterases-4 inhibitor.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) on erectile insufficiencyinclude phosphodiesterases-5 inhibitor.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) on shock include elastaseinhibitor.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) on colitis include steroidpreparation, phosphodiesterases-4 inhibitor, nonsteroid-basedantiphlogistic, thromboxane A₂ receptor antagonist, leukotriene receptorantagonist, angiotensin II antagonist, angiotensin converting enzymeinhibitor, and diuretic.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) on hypertension includecalcium antagonist, angiotensin II antagonist, angiotensin convertingenzyme inhibitor, phosphodiesterases-4 inhibitor, and diuretic.

Examples of the phosphodiesterases-4 inhibitor include rolipram,cilomilast (trade name: Ariflo), Bay 19-8004, NIK-616, cilomilast(BY-217), cipamfylline (BGL-61063), atizolam (CP-80633), SCH-351591,YM-976, V-11294A, PD-168787, D-4386, and IC-485.

Examples pf the phosphodiesterases-5 inhibitor include sildenafil.

Examples of the bisphonate preparation include sodium alendronate,disodium chlodronate, disodium pamidronate, disodium ethydronate,ivandronate, disodium incadronate, minodronate, olpadronate, sodiumrisedronate, tildronate, and zoledronate.

Examples of the calcitonin preparation include calcitonin, andelcatonin.

Examples of the prostaglandins (hereinafter abbreviated as “PG”) includePG receptor agonist, and PG receptor antagonist.

Examples of PG receptor include PGE receptors (EP₁, EP₂, EP₃, EP₄), PGDreceptors (DP), PGF receptors (FP), and PGI receptors (IP).

Examples of the steroid preparation for external application includeclobetasol propionate, diflorasone acetate, fluocinonide, monometasonefurancarboxylate, betamesone dipropionate, betamesone butyropropionate,betamesone valerate, difluprednate, budesonide, diflucortolone valerate,amcinonide, halcinonide, dexamethasone, dexamethasone propionate,dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate,hydrocortisone butyrate, hydrocortisone acetopropionate, deprodonepropionate, prednisolone valeroacetate, fluocinolone acetonide,beclometasone dipropionate, triamcinonide acetonide, flumethasonepivalate, prednisolone, beclometasone propionate, and fludroxycortide.

Examples of the steroid preparation for internal use or injectioninclude cortisone acetate, hydrocortisone, hydrocortisone sodiumphosphate, hydrocortisone sodium succinate, fludrocortisone acetate,prednisolone, prednisolone acetate, prednisolone sodium succinate,prednisolone butylacetate, prednisolone sodium phosphate, halopredonacetate, methyl prednisolone, methyl prednisolone acetate, methylprednisolone sodium succinate, triamicinolon, triamicinolon acetate,triamicinonolon acetonide, dexamethasone, dexamethasone acetate,dexamethasone sodium phosphate, dexamethasone palmitate, paramethasoneacetate, and betamethasone.

Examples of the steroid preparation as an inhalant includebeclomethasone propionate, fluticasone propionate, budesonide,flunisolide, triamicinolon, ST-126P, ciclesonide, dexamethasonepalomitionate, monometasone furancarboxylate, prasterone sulfonate,deflazacort, methyl prednisolone sreptanate, and methyl prednisolonesodium succinate.

Examples of the β₂ adrenoreceptor stimulant include fenoterolhydrobromide, salbutamol sulfate, terbutaline sulfate, formoterolfumarate, salmeterol xinafoate, isoprotenol sulfate, orciprenalinsulfate, chloroprenalin sulfate, epinephrine, trimetoquinolhydrochloride, hexoprenalinmesyl sulfate, procaterol hydrochloride,tulobuterol hydrochloride, tulobuterol, pirbuterol hydrochloride,clenbuterol hydrochloride, mabuterol hydrochloride, ritodrinehydrochloride, bambuterol, dopexamin hydrochloride, meradrin tartrate,AR-C68397, levosalbutamol, R,R-formoterol, KUR-1246, KUL-7211,AR-C89855, and S-1319.

Examples of the leukotriene receptor antagonist include pranlukasthydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757,CD-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496,BIIL-284, and ONO-4057.

Examples of the thromboxane synthesis enzyme inhibitor include ozagrelhydrochloride, and imitrodast sodium.

Examples of the thromboxane A₂ receptor antagonist include seratrodast,ramatroban, domitroban calcium dihydrate, and KT-2-962.

Examples of the mediator liberation inhibitor include tranilast, sodiumcromoglicate, anlexanox, repirinast, ibudilast, tazanolast, andpemilolast sodium.

Examples of the antihistamines include ketotifen fumarate, mequitazine,azelastine hydrochloride, oxatomide, terfenadine, emedastine fumarate,epinastine hydrochloride, astemizole, ebastin, cetirizine hydrochloride,bepotastine, fexofenadine, lolatadine, deslolatadine, olopatadinehydrochloride, TAK-427, ZCR-2060, NIP-530, mometasone furoate,mizolastine, BP-294, andolast, auranofin, and acribastin.

Examples of the xanthine derivatives include aminophylline,thoeophyline, doxophylline, cipamphilline, and diprophilline.

Examples of the anticholinergic preparation include ipratropium bromide,oxitropium bromide, flutropium bromide, temiverine, tiotropium bromide,and revatropate (UK-112166).

Examples of the cytokine inhibitor include suplatast tosilate (tradename: IPD).

Examples of the expectorant include foeniculated ammonia spirit, sodiumhydrogencarbonate, bromhexine hydrochloride, carbocisteine, ambroxolhydrochloride, extended-release ambroxol hydrochloride, methylcysteinehydrochloride, acetyl cysteine, L-ethylcysteine hydrochloride, andtyloxapol.

Examples of the growth factors include fibroblast growth factor (FGF),vascular endothelium growth factor (VEGF), hepatocyte growth factor(HGF), and insulin-like growth factor.

Examples of the nonsteroid-based antiphlogistic include sasapyrine,sodium salicylate, aspirin, aspirin dialuminate formulation, diflunisal,indomethacin, suprofen, ufenamate, dimethylisopropyl azulen, bufexamac,felbinac, diclofenac, tolmetin sodium, Clinoril, fenbufen, napmetone,proglumetacin, indomethacin farnesil, acemetacin, proglumetacin maleate,amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol,naproxen, flurbiprofen, flurbiprofen axethyl, ketoprofen, fenoprofencalcium, tiaprofenen, oxaprozin, pranoprofen, loxoprofen sodium,aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate,tolfenamic acid, floctafenine, ketophenylbutazone, oxyfenbutazone,piroxicam, tenoxicam, anpiroxicam, napageln cream, epirizole, tiaramidehydrochloride, tinoridine hydrochloride, emorfazone, sulpyrine,Migrenin, Saridon, Sedes G, Amipylo N, Sorbon, pyrine systemantipyretics, acetaminophen, phenacetin, dimethothiazine mesylate,simetride formulation, and antipyrine system antipyretics.

Examples of the diuretic include mannitol, furosemide, acetazolamide,diclofenamide, matazolamide, trichlormethiazide, mefruside,spinolactone, and aminophylline.

The weight proportion of the compound represented by formula (I-1),(I-2) or (I-3) and the other pharmaceutical preparations is notspecifically limited.

Arbitrary two or more of the other pharmaceutical preparations may beadministered in combination.

Examples of the other pharmaceutical preparations for compensating forand/or enhancing the preventive and/or treatment effect of the compoundrepresented by formula (I-1), (I-2) or (I-3) include not only thosewhich have so far been found but also those which will be found on thebasis of the aforementioned mechanism.

In order to use the compound of the invention represented by formulae(I-2) and (I-3) or the compound represented by formula (I-1), (I-2) or(I-3) in combination with the other pharmaceutical preparations, thesecompounds are normally administered to the entire or local part of humanbody orally or parenterally.

The dose of these compounds depends on the age, weight and symptom ofthe patient, the remedial value, the administration method, thetreatment time, etc. In practice, however, these compounds areadministered orally once or several times per day each in an amount offrom 1 ng to 100 mg per adult, parenterally once or several times perday each in an amount of from 0.1 ng to 00 mg per adult or continuouslyadministered into vein for 1 hour to 24 hours per day.

It goes without saying that the dose of these compounds may be less thanthe aforementioned value or may need to exceed the aforementioned rangebecause the dose varies under various conditions as mentioned above.

When the compounds of the invention represented by formulae (I-2) and(I-3) or the compound represented by formula (I-1), (I-2) or (I-3) isadministered in combination with the other pharmaceutical preparations,they are used in the form of solid or liquid agent for oraladministration, injection, agent for external application, suppository,dye drops or inhalant for parenteral administration or the like.

Examples of the solid agent for oral administration include tablet,pill, capsule, powder, and pellet. Examples of the capsule include hardcapsule, and soft capsule.

In such a solid agent for internal application, one or more activematerials are used in the form of preparation produced by an ordinarymethod singly or in admixture with a vehicle (e.g., lactose, mannitol,glucose, microcrystalline cellulose, starch), binder (e.g.,hydroxypropyl cellulose, polyvinyl pyrrolidone, magnesiummetasilicoaluminate), disintegrant (e.g., calcium fibrinoglycolate),glidant (e.g., magnesium stearate), stabilizer, dissolution aid (e.g.,glutamic acid, aspartic acid) or the like. The solid agent may be coatedwith a coating agent (e.g., white sugar, gelatin, hydroxypropylcellulose, hydroxypropyl methyl cellulose phthalate) or two or morelayers. Alternatively, the solid agent may be capsulized by anabsorbable material such as gelatin.

Examples of the liquid agent for oral administration includepharmaceutically acceptable aqueous solution, suspension, emulsion,syrup, and elixir. In such a liquid agent, one or more active agents aredissolved, suspended or emulsified in a commonly used diluent (e.g.,purified water, ethanol, mixture thereof). Furthermore, such a liquidagent may comprise a wetting agent, a suspending agent, an emulsifier, asweetening agent, a flavor, a preservative, a buffer, etc.

The agent for parenteral administration may be in the form of, e.g.,ointment, gel, cream, wet compress, paste, liniment, nebula, inhalant,spray, eye drops, collunarium or the like. These agents each contain oneor more active materials and are prepared by any known method orcommonly used formulation.

The ointment is prepared by any known or commonly used formulation. Forexample, one or more active materials are titurated or dissolved in abase to prepare such an ointment. The ointment base is selected fromknown or commonly used materials. In some detail, higher aliphatic acidor higher aliphatic acid ester (e.g., adipic acid, myristic acid,palmitic acid, stearic acid, oleic acid, adipic acid ester, myristicacid ester, palmitic acid ester, stearic acid ester, oleic acid ester),wax (e.g., beeswax, whale wax, ceresin), surface active agent (e.g.,polyoxyethylenealkyletherphosphoric acid ester), higher alcohol (e.g.,cetanol, stearyl alcohol, setostearyl alcohol), silicon oil (e.g.,dimethyl polysiloxane), hydrocarbon (e.g., hydrophilic petrolatum, whitepetrolatum, purified lanolin, liquid paraffin), glycol (e.g., ethyleneglycol, diethylene glycol, propylene glycol, polyethylene glycol,macrogol), vegetable oil (e.g., castor oil, olive oil, sesame oil,turpentine oil), water, absorption accelerator and rash preventive maybe used singly or in admixture of two or more thereof The base mayfurther comprise a humectant, a preservative, a stabilizer, anantioxidant, a perfume, etc.

The gel is prepared by any known or commonly used formulation. Forexample, one or more active materials are dissolved in a base to preparesuch a gel. The gel base is selected from known or commonly usedmaterials. For example, lower alcohol (e.g., ethanol, isopropylalcohol), gelling agent (e.g., carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose, ethyl cellulose), neutralizing agent(e.g., triethanolamine, diisopropanolamine), surface active agent (e.g.,polyethylene glycol monostearate), gum, water, absorption accelerator,and rash preventive are used singly or in admixture of two or morethereof The gel base may further comprise a humectant, an antioxidant, aperfume, etc.

The cream is prepared by any known or commonly used formulation. Forexample, one or more active materials are dissolved in a base to preparesuch a cream. The cream base is selected from known or commonly usedmaterials. For example, higher aliphatic acid ester, lower alcohol,hydrocarbon, polyvalent alcohol (e.g., propylene glycol, 1,3-butyleneglycol), higher alcohol (e.g., 2-hexyl decanol, cetanol), emulsifier(e.g., polyoxyethylene alkyl ether, aliphatic acid ester), water,absorption accelerator, and rash preventive are used singly or inadmixture of two or more thereof The cream base may further comprise ahumectant, an antioxidant, a perfume, etc.

The wet compress is prepared by any known or commonly used formulation.For example, one or more active materials are dissolved in a base toprepare a kneaded mixture which is then spread over a support to preparesuch a wet compress. The wet compress base is selected from known orcommonly used materials. For example, thickening agent (e.g.,polyacrylic acid, polyvinyl pyrrolidone, gum arabic, starch, gelatin,methyl cellulose), wetting agent (e.g., urea, glycerin, propyleneglycol), filler (e.g., kaolin, zinc oxide, talc, calcium, magnesium),water, dissolution aid, tackifier, and rash preventive may be usedsingly or in admixture of two or more thereof The wet compress base mayfurther comprise a humectant, an antioxidant, a perfume, etc.

The pasting agent is prepared by any known or commonly used formulation.For example, one or more active materials are dissolved in a base toprepare a kneaded mixture which is then spread over a support to preparesuch a pasting agent. The pasting agent base is selected from known orcommonly used materials. For example, polymer base, fat and oil, higheraliphatic acid, tackifier and rash preventive may be used singly or inadmixture of two or more thereof The pasting agent base may furthercomprise a humectant, an antioxidant, a perfume, etc.

The liniment is prepared by any known or commonly used formulation. Forexample, one or more active materials are dissolved, suspended oremulsified in water, alcohol (e.g., ethanol, polyethylene glycol),higher aliphatic acid, glycerin, soap, emulsifier, suspending agent,etc., singly or in combination of two or more thereof, to prepare such aliniment. The liniment may further comprise a humectant, an antioxidant,a perfume, etc.

The nebula, inhalant and spray each may comprise a stabilizer such assodium hydrogensulfite and a buffer capable of providing isotonicitysuch as isotonic agent (e.g., sodium chloride, sodium citrate, citricacid). For the process for the preparation of spray, reference can bemade to U.S. Pat. Nos. 2,868,691 and 3,095,355. These agents may be inthe form of aerosol.

The injection for parenteral administration may be in the form ofsolution, suspension, emulsion or solid injection to be dissolved orsuspended in a solvent in use. The injection is prepared by dissolving,suspending or emulsifying one or more active materials in a solvent. Assuch a solvent there may be used distilled water for injection,physiological saline, vegetable oil, alcohol such as propylene glycol,polyethylene glycol and ethanol, etc., singly or in combination. Theinjection may further comprise a stabilizer, a dissolution aid (e.g.,glutamic acid, aspartic acid, Polysolvate 80 (trade name)), a suspendingagent, an emulsifier, a soothing agent, a buffer, a preservative, etc.The injection is sterilized at the final step or prepared by an asepticprocess. Alternatively, an aseptic solid agent such as freeze-driedproduct which has previously been prepared may be rendered aseptic ordissolved in an aseptic distilled water for injection or other solventbefore use.

The eye drops for parenteral administration may be in the form ofliquid, suspension, emulsion or ointment or may be dissolved in asolvent in use.

These eye drops are prepared by any known method. For example, one ormore active materials are dissolved, suspended or emulsified in asolvent. As such a solvent for eye drops there may be used sterilizedpurified water, physiological saline and other aqueous or nonaqueoussolvents (e.g., vegetable oil), singly or in combination. The eye dropsmay comprise an isotonic agent (e.g., sodium chloride, concentratedglycerin), a buffering agent (e.g., sodium phosphate, sodium acetate), asurface active agent (e.g., Polysolvate 80 (trade name), polyoxylstearate 40, polyoxyethylene-hardened castor oil), a stabilizer (sodiumcitrate, sodium edetate), a preservative (e.g., benzalconium chloride,Paraben), etc. properly selectively as necessary. The eye drops aresterilized at the final step or prepared by an aseptic process.Alternatively, an aseptic solid agent such as freeze-dried product whichhas previously been prepared may be rendered aseptic or dissolved in anaseptic distilled water for injection or other solvent before use.

The inhalant for parenteral administration may be in the form ofaerosol, powder for inhalation or liquid for inhalation. The liquid forinhalation may be dissolved or suspended in water or other proper mediumin use.

These inhalants are prepared by an known method.

For example, the liquid for inhalation is prepared from materialsproperly selected from preservatives (e.g., benzalconium chloride,Paraben), colorants, buffering agents (e.g., sodium phosphate, sodiumacetate), isotonic agents (e.g., sodium chloride, concentratedglycerin), thickening agents (e.g., carboxyvinyl polymer), absorptionaccelerators, etc. as necessary.

The powder for inhalation is prepared from materials properly selectedfrom glidants (e.g., stearic acid and salt thereof), binders (e.g.,starch, dextrin), vehicles (e.g., lactose, cellulose), colorants,preservatives (e.g., benzalconium chloride, Paraben), absorptionaccelerators, etc., if necessary.

In order to administer the liquid for inhalation, a sprayer (e.g.,atomizer, nebulizer) is normally used. In order to administer the powderfor inhalation, a powder inhaler is normally used.

Other examples of the composition for oral administration includesuppository for rectal administration and pessary for vaginaladministration prepared by an ordinary formulation comprising one ormore active materials.

Local Application:

Referring to the local administration of the invention, EP₄ agonist maybe locally administered to site of disease (particularly bone diseasesin which the amount of bone is decreased). The form of EP₄ agonist isnot limited to its administration method. EP₄ agonist may be in the formof injection, solid agent such as embedding agent, pellet and powderointment to be administered to intramuscular, subcutaneous or articularsite.

The extended-release preparation is not limited to its form so far asEP₄ agonist can be continuously administered to site of disease(particularly bone diseases in which the amount of bone is decreased).The extended-release preparation may be in the form of, e.g.,extended-release injection (e.g., microcapsuled preparation,microspheric preparation, nanospheric preparation), embeddingpreparation (e.g., film-like preparation) or the like.

The microcapsuled preparation, microspheric preparation and nanosphericpreparation of the invention each are a finely divided pharmaceuticalcomposition with an in vivo degradable polymer comprising as activecomponents the compound represented by formula (I-1), (I-2) or (I-3)optionally in combination with other pharmaceutical preparations.

Examples of the in vivo degradable polymer of the invention includealiphatic acid ester polymers and copolymers thereof, polyacrylic acidesters, polyhydroxybutyric acids, polyalkylene oxalates,polyorthoesters, polycarbonates, and polyaminoacids. These compounds maybe used singly or in admixture of two or more thereof Examples of thealiphatic acid ester polymers and copolymers thereof include polylacticacid, polyglycolic acid, polycitric acid, polymalic acid, and lacticacid-glycolic acid copolymer. These compounds may be used singly or inadmixture of two or more thereof. Besides these compounds,poly-α-cyanoacrylic acid esters, poly-β-hydroxybutyric acids,polytrimethyleneoxates, polyorthoesters, polyorthocarbonates,polyethylene carbonates, poly-γ-benzyl-L-glutamic acids andpoly-L-alanines may be used singly or in admixture of two or morethereof Preferred among these compounds are polylactic acids,polyglycolic acids and lactic acid-glycolic acid copolymers, morepreferably lactic acid-glycolic acid copolymers.

The average molecular weight of these in vivo degradable polymers to beused in the invention is preferably from about 2,000 to 800,000, morepreferably from about 5,000 to 200,000. For example, the polylactic acidpreferably has a weight-average molecular weight of from about 5,000 to100,000, more preferably from about 6,000 to 50,000. The polylactic acidcan be synthesized according to any known preparation method per se. Inthe lactic acid-glycolic acid copolymer, the composition ratio of thelactic acid to the glycolic acid is preferably from about 100/0 to 50/50(w/w), particularly from about 90/10 to 50/50. The weight-averagemolecular weight of the lactic acid-glycolic acid copolymer ispreferably from about 5,000 to 100,000, more preferably from about10,000 to 80,000. The lactic acid-glycolic acid copolymer can besynthesized according to any known preparation method per se.

The term “weight-average molecular weight” as used herein is meant toindicate molecular weight in polystyrene equivalence determined by gelpermeation chromatography (GPC).

The aforementioned in vivo degradable polymer may be changed dependingon the intensity of pharmacological activity of the compoundsrepresented by formulae (I-1), (I-2) and (I-3) and the desired medicinesto be released so far as the aforementioned aims of the invention areaccomplished. For example, the in vivo degradable polymer may be used inan amount of from about 0.2 to 10,000 times, preferably from about 1 to1,000 times, more preferably from about 1 to 100 times (by weight) thatof the physiologically active material.

Examples of the process for the preparation of microspheric,microcapsuled and nanospheric preparations include submerged dryingmethod (e.g., o/w method, w/o method, w/o/w method), phase separationmethod, spray drying method, granulation method by ulractritical fluid,and methods analogous thereto.

The submerged drying method (o/w method) and spray drying method will befurther described hereinafter.

-   (1) In the submerged drying method (o/w method), a solution of an in    vivo degradable polymer in an organic solvent is prepared at first.    The organic solvent to be used in the preparation of the    microspheric, microcapsuled and nanospheric preparations preferably    has a boiling point of 120° C. or less. Examples of the organic    solvent employable herein include halogenated hydrocarbons (e.g.,    dichloromethane, chloroform), aliphatic esters (e.g., ethyl    acetate), ethers, aromatic hydrocarbons, and ketones (e.g.,    acetone). These compounds may be used in admixture of two or more at    a proper ratio. Preferred among these organic solvents are    dichloromethane and acetonitrile, particularly dichloromethane. The    concentration of the in vivo degradable polymer in the organic    solution depends on the molecular weight of the in vivo degradable    polymer, the kind of the organic solvent, etc. but is normally    predetermined to be from about 0.01 to 80% (v/w), preferably from    about 0.1 to 70% (v/w), more preferably from about 1 to 60% (v/w).

The compound represented by formula (I-1), (I-2) or (I-3) is then addedto and dissolved in the solution of the in vivo degradable polymer in anorganic solvent thus obtained, optionally in combination with otherpharmaceutical preparations. The amount of the compound represented byformula (I-1), (I-2) or (I-3) to be added optionally in combination withthe other pharmaceutical preparations depends on the kind of thepharmaceutical preparations to be added, the action of thepharmaceutical preparations in osteogenesis, the duration of the action,etc. but is normally from about 0.001% to 90% (w/w), preferably fromabout 0.01% to 80% (w/w), more preferably from about 0.3 to 30% (w/w) ascalculated in terms of concentration in the solution of in vivodegradable polymer in an organic solvent.

Subsequently, the organic solution thus prepared is added to an aqueousphase which is then processed by an agitator, emulsifier or the like toform an o/w emulsion. The volume of the aqueous phase during thisprocedure is predetermined to be from about 1 to 10,000 times,preferably from about 2 to 5,000 times, particularly from about 5 to2,000 times that of the oil phase. An emulsifier may be added to theaqueous phase which is an external phase. As such an emulsifier theremay be normally used any material capable of forming a stable o/wemulsion. Examples of the emulsifier employable herein include anionicsurface active agents, nonionic surface active agents, polyoxyethylenecastor oil derivatives, polyvinyl pyrrolidone, polyvinyl alcohol,carboxymethyl cellulose, lecitine, and gelatin. These compounds may beused in proper combination. The concentration of the emulsifier in theexternal aqueous phase is preferably from about 0.001% to 20% (w/w),more preferably from about 0.01% to 10% (w/w), particularly from about0.05% to 5% (w/w).

The evaporation of the solvent which is an oil phase can be accomplishedby any commonly used method. In some detail, the evaporation of thesolvent may be effected at ordinary pressure or gradually fallingpressure with stirring by an agitator, magnetic stirrer or the like ormay be effected while the pressure is being adjusted using a rotaryevaporator. The microspheric preparation thus obtained is thenfractionated by centrifugal separation or filtration. The microsphericpreparation is washed with a surface active agent solution, alcohol orthe like several times to remove the free compound represented byformula (I-1), (I-2) or (I-3), optionally in combination with otherpharmaceutical preparations, and the emulsifier from the surfacethereof, again dispersed in distilled water or a dispersant containing avehicle (e.g., mannitol, sorbitol, lactose), and then freeze-dried. Inthe aforementioned o/w method, the microspheric preparation may beprepared by a method involving the dispersion of the compoundrepresented by formula (I-1), (I-2) or (I-3) in a solvent of an in vivodegradable polymer in an organic solvent, optionally in combination withother pharmaceutical preparations, i.e., s/o/w method.

-   (2) In order to prepare the microspheric preparation by the spray    drying method, an organic solvent or emulsion having the in vivo    degradable polymer and the compound represented by formula (I-1),    (I-2) or (I-3), optionally in combination with other pharmaceutical    preparations, dissolved therein is sprayed into the drying chamber    of a spray dryer (spray dryer) through a nozzle so that the organic    solvent or water in the atomized droplets is evaporated in an    extremely short period of time to prepare a microspheric    preparation. Examples of the nozzle employable herein include two    liquid nozzle, pressure nozzle, and rotary disc. It is useful to    spray an organic solvent or an aqueous solution of an aggregation    inhibitor (e.g., mannitol, lactose, gelatin) at the same time with    the spray of o/w emulsion as necessary for the purpose of inhibiting    the aggregation of microspheres. The microspheric preparation thus    obtained is then put under reduced pressure optionally under heating    to remove water and solvent therefrom.

Examples of the film-like preparation include film-like materialobtained by dissolving the aforementioned in vivo degradable polymer andcompound represented by formula (I-1), (I-2) or (I-3), optionally incombination with other pharmaceutical preparations, in an organicsolvent, and then subjecting the solution to evaporation to dryness andgelled material obtained by dissolving the aforementioned in vivodegradable polymer and compound represented by formula (I-1), (I-2) or(I-3), optionally in combination with other pharmaceutical preparations,in a proper solvent, and then adding a granulating agent (e.g.,cellulose, polycarbonate) to the solution.

The microsphere, microcapsule and nanosphere of the invention may beused as they are. Alternatively, a spherical, rod-like, acicular,pelletized, film-like or cream-like pharmaceutical composition may beprocessed as a starting material to provide preparations in variousforms.

Furthermore, this preparation may be used as a parenteral for localadministration (e.g., injection, solid agent such as embedding agent,pellet and powder, liquid agent such as suspension, ointment, etc. to beadministered to intramuscular, subcutaneous, organic or articular site).For example, in order to make an injection from the microsphericpreparation, the microspheric preparation is suspended with adispersant, a preservative, an isotonic agent, a buffer, a pH adjustor,etc. to make an aqueous suspension as a practical preparation forinjection. Alternatively, the microspheric preparation may be dispersedwith a vegetable oil optionally in admixture with a phospholipid such aslecitine or with a middle-chain aliphatic acid triglyceride (e.g.,Mygliol-812) to make an oil suspension as an injection which can bepractically used.

The particle diameter of the microspheric preparation may be arbitraryso far as it suffices the desired dispersibility and passage throughsyringe if the preparation is used as a suspension for injection. By wayof example, the average particle diameter of the microsphericpreparation is from about 0.1 to 300 μm, preferably from about 1 to 150μm, more preferably from about 2 to 100 μm. The pharmaceuticalcomposition of the invention is preferably in the form of suspension asmentioned above. The pharmaceutical composition of the invention is alsopreferably in particulate form. This is because the pharmaceuticalcomposition gives less excessive pain to patients when administeredthrough a syringe for use in ordinary hypodermic or intramuscularinjection. It is particularly preferred that the pharmaceuticalcomposition of the invention be in the form of injection. Examples ofthe method for rendering the microspheric preparation aseptic includemethod which is aseptic throughout the entire steps, method involvingsterilization by gamma rays, and method involving the addition ofpreservative. However, the invention is not limited to these methods.

The pharmaceutical composition of the invention can be used for thetreatment of bone diseases in which the amount of bone is decreasedbecause the compound represented by formula (I-1), (I-2) or (I-3),optionally in combination with other pharmaceutical preparations, can begradually released normally for 1 week to 3 months, though depending onthe kind and added amount of the in vivo degradable polymer. Among thesebone disease treatments, the treatment of fracture often requires thatthe affected part be fixed and covered with a plaster bandage and theadministration of pharmaceutical preparations be conducted only oncerather than frequently. Accordingly, the pharmaceutical preparationsthus administered are required to accelerate treatment continuously.Thus, the pharmaceutical composition of the invention is usefulparticularly in this treatment.

The dose of the pharmaceutical composition of the invention depends onthe kind, content and form of the compound represented by formula (I-1),(I-2) or (I-3), optionally in combination with other pharmaceuticalpreparations, the duration of release of pharmaceutical preparations,the animal to be administered, etc., but may be the effective amount ofthe compound represented by formula (I-1), (I-2) or (I-3), optionally incombination with other pharmaceutical preparations. When administered tofracture as a microspheric preparation, for example, one time dose foradult (weight: 50 kg) is from about 0.001 mg to 500 mg, preferably fromabout 0.01 mg to 50 mg as calculated in terms of effective component.The pharmaceutical composition of the invention may be administered once1 week to 3 months in the aforementioned amount.

BEST MODE FOR CARRYING OUT THE INVENTION

The following Reference Examples and Examples are intend to illustrate,but not to limit the present invention.

The solvents in parentheses at chromatographic separations section showthe developing or eluting solvents and the ratios of the solvents usedare indicated by volume.

Without special explanation, NMR data was determined in CDCl₃ solution.And the solvents in parentheses at NMR data section show solvents usedin determination.

TBS is t-butyldimethylsilyl, THP is tetrahydropyran-2-yl, Boc ist-butoxycarbonyl, Me is methyl, Et is ethyl, Ac is acetyl, Bu is butyl,Ms is mesyl and TMS is trimethylsilyl.

REFERENCE EXAMPLE 1 (5R)-5-t-Butyldimethylsilyloxymethylpyrrolidin-2-one

Under atmosphere of argon, a solution of(5R)-5-hydroxymethylpyrollidin-2-one (10 g) and imidazole (8.8 g) in drydimethylformamide (50 mL) was added by a solution oft-butyldimethylsilyl chloride (15.6 g) in dry dimethylformamide (50 mL)at room temperature, and the mixture was stirred for 5 hours. To themixture, a mixed solvent of ethyl acetate and hexane was added. Thediluted solution was washed with water and brine successively, driedover an anhydrous sodium sulfate, concentrated under reduced pressure togive the title compound (21.41 g) having the following physical data.

TLC: Rf 0.52 (Ethyl Acetate).

REFERENCE EXAMPLE 29-Oxo-13-t-butyldimethylsilyloxy-14,15,16,17,18,19,20-heptanor-8-azaprostanoicacid ethyl ester

Under atmosphere of argon, a suspension of sodium hydride (3.42 g; 63.1%in oil) in dry tetrahydrofuran (90 mL) was added by a solution of thecompound prepared in Reference Example 1 (20.8 g) in dry tetrahydrofuran(90 mL) at room temperature. Then dimethylformamide (180 mL) was addedto the mixture, and the mixture was stirred for 45 minutes at 50° C. Tothe mixture, a solution of 7-bromoheptanoic acid ethyl ester (22.4 g) indimethylformamide (20 mL) was added, and the mixture was stirred for 4hours. After cooling, a mixed solvent of ethyl acetate and hexane wasadded. The organic layer was washed with 0.5N hydrochloric acid, waterand brine successively, dried over an anhydrous sodium sulfate,concentrated under reduced pressure to give the title compound (34.9 g)having the following physical data.

TLC: Rf 0.51 (Ethyl Acetate:Hexane=2:1).

REFERENCE EXAMPLE 39-Oxo-13-hydroxy-14,15,16,17,18,19,20-heptanor-8-azaprostanoic acidethyl ester

To a solution of the compound prepared in Reference Example 2 (34.9 g)in ethanol (43 mL), p-toluenesulfonic acid (2.96 g) was added, and themixture was stirred overnight at 50° C. It was cooled to roomtemperature, the mixture was added by triethylamine (2.4 mL),concentrated under reduced pressure and was purified by columnchromatography on silica gel (from ethyl acetate:hexane=1:1 to ethylacetate only) to give the title compound (13.15 g) having the followingphysical data.

TLC: Rf 0.18 (Ethyl Acetate); NMR: δ 4.12 (q, J=7 Hz, 2H), 3.85-3.6 (m,4H), 3.05-2.9 (m, 1H), 2.55-2.4 (m, 1H), 2.4-2.25 (m, 3H), 2.2-2.05 (m,1H), 2.0-1.9 (m, 1H), 1.85-1.7 (br, 1H), 1.7-1.2 (m, 8H), 1.27 (t, J=7Hz, 3H).

REFERENCE EXAMPLE 49-Oxo-12-formyl-13,14,15,16,17,18,19,20-octanor-8-azaprostanoic acidethyl ester

Under atmosphere of argon, a solution of the compound prepared inReference Example 3 (1.25 g) in ethyl acetate (10 mL) and drydimethylsulfoxide (7 mL) was added by diisopropylethylamine (5.1 mL).Then sulfur trioxide pyridine complex (2.32 g) was added to the mixtureon ice bath, and the mixture was stirred for 1 hour at 0˜15° C. Smallamount of water was added to the reaction mixture, the reaction wasterminated. Chloroform (10 mL) was added to the mixture. The organiclayer was washed with 0.5N hydrochloric acid, dried over an anhydroussodium sulfate, concentrated under reduced pressure to give the titlecompound (1.25 g) having the following physical data, which was used forthe next reaction without purification.

TLC: Rf 0.45 (Chloroform:Methanol=9:1).

REFERENCE EXAMPLE 5(13E)-9,15-Dioxo-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid ethyl ester

Under atmosphere of argon, a solution of3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl ester(1.81 g) in dry tetrahydrofuran (35 mL) was added by sodium hydride (222mg; 63.1% in oil), and the mixture was stirred for 30 minutes at roomtemperature. To the suspension, a solution of the compound prepared inReference Example 4 (1.25 g) in tetrahydrofuran (5 mL) was added, andthe mixture was stirred for 3 hours. Then ethyl acetate was added to themixture. The diluted solution was washed with water and brinesuccessively, dried over an anhydrous sodium sulfate, concentrated underreduced pressure and was purified by column chromatography on silica gel(ethyl acetate: hexane=from 2:1 to 3:1, then ethyl acetate only) to givethe title compound (1.23 g) having the following physical data.

TLC: Rf 0.72 (Chloroform:Methanol=9 1); NMR: δ 7.35-7.10 (m, 4H), 6.65(dd, J=16, 8 Hz, 1H), 6.23 (d, J=16 Hz, 1H), 4.42 (s, 2H), 4.2-4.1 (m,3H), 3.85 (s, 2H), 3.6-3.5 (m, 1H), 3.38 (s, 3H), 2.8-2.65 (m, 1H),2.5-2.2 (m, 5H), 1.85-1.7 (m, 1H), 1.7-1.5 (m, 2H), 1.5-1.2 (m, 9H).

EXAMPLE 1(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid ethyl ester

Under atmosphere of argon, a solution of the compound prepared inReference Example 5 (1.23 g) in dry tetrahydrofuran (10 mL) was added bya 1.0M (R)-2-methyl-CBS-oxazaborolidine/toluene solution (0.57 mL) atroom temperature. Then borane tetrahydrofuran complex (2.32 mL) wasdropped to the mixture, and the mixture was stirred for 45 minutes. Tothe mixture, 1N hydrochloric acid and ethyl acetate was added. Theorganic layer was washed with water and brine successively, dried overan anhydrous sodium sulfate, concentrated under reduced pressure and waspurified by column chromatography on silica gel (from ethyl acetate onlyto ethyl acetate:hexane=19:1) to give the title compound (1.05 g) havingthe following physical data.

TLC: Rf 0.60 (Chloroform:Methanol=9:1); NMR: δ 7.38-7.10 (m, 4H), 5.73(dd, J=15.3, 6.0 Hz, 1H), 5.50 (dd, J=15.3, 8.0 Hz, 1H), 4.48-4.35 (m,3H), 4.17-3.98 (m, 3H), 3.53-3.36 (m, 4H), 2.92-2.68 (m, 3H), 2.44-2.05(m, 6H), 1.81-1.20 (m, 12H).

EXAMPLE 2(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

A solution of the compound prepared in Example 1 (1.05 g) in methanol (5mL) was added by 2N aqueous sodium hydroxide (4 ml), and the mixture wasstirred overnight. To the mixture, diethyl ether (10 mL) and water (20mL) was added, and the mixture was stirred. 1N hydrochloric acid wasadded to the aqueous layer to acidify, then extracted by ethyl acetate.The organic layer was washed with water and brine successively, driedover an anhydrous sodium sulfate, concentrated under reduced pressureand was purified by column chromatography on silica gel (from chloroformonly to chloroform:methanol=100:1, then 50:1, then 25:1) to give thetitle compound (837 mg) having the following physical data.

TLC: Rf 0.41 (Chloroform:Methanol=9:1); NMR: δ 7.36-7.11 (m, 4H), 5.75(dd, J=15.3, 6.0 Hz, 1H), 5.51 (dd, J=15.3, 8.0 Hz, 1H), 4.49-4.38 (m,3H), 4.08-3.99 (m, 1H), 3.50-3.36 (m, 4H), 2.94-2.75 (m, 3H), 2.49-2.14(m, 6H), 1.79-1.20 (m, 9H).

EXAMPLE 2(a) to EXAMPLE 2(bbb)

By the same procedure as describe in Reference Examples 1, 2, 3, 45,Examples 1 and 2 using 7-bromoheptanoic acid ethyl ester orcorresponding halide derivatives, and3-(3-methoxymethylphenyl)-3-oxopropylphosphonic acid dimethyl ester orcorresponding phosphonic ester derivatives, the compound of the presentinvention having the following physical data were obtained.

EXAMPLE 2(a) (5S,15α,13E)-5-Methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.28 (Methanol:Chloroform=1:10); NMR: δ 7.40-7.10 (m, 4H), 5.78(dd, J=15.2, 5.2 Hz, 1H), 5.55 (dd, J=15.2, 8.4 Hz, 1H), 4.50-4.35 (m,1H), 4.46 (s, 2H), 4.10-3.95(m, 1H), 3.60-3.35 (m, 1H), 3.42 (s, 3H),3.00-2.70 (m, 4H), 2.50-2.10 (m, 5H), 1.80-1.00 (m, 8H), 0.91 (d, J=5.8Hz, 3H).

EXAMPLE 2(b)(15α,13E)-5,5-Dimethyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.38 (Chloroform:Methanol=9:1); NMR: δ 7.33-7.12 (m, 4H), 5.78(dd, J=15, 5Hz, 1H), 5.59 (dd, J=15, 8 Hz, 1H), 4.48 (s, 2H), 4.45-4.36(m, 1H), 4.12-4.03 (m, 1H), 3.51 (dt, J=12, 5 Hz, 1H), 3.43 (s, 3H),2.91-2.81 (m, 2H), 2.76 (dd, J=14, 8 Hz, 1H), 2.47-2.10 (m, 5H),1.78-1.63 (m, 1H), 1.61-1.40 (m, 3H), 1.32-1.10 (m, 3H), 0.92 (s, 3H),0.89 (s, 3H).

EXAMPLE 2(c)(15α,13E)-5,5-Ethano-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.38 (Chloroform:Methanol=9:1); NMR: δ 7.33-7.13 (m, 4H), 5.81(dd, J=15, 5 Hz, 1H), 5.61 (dd, J=15, 8 Hz, 1H), 4.46 (s, 2H), 4.48-4.39(m, 1H), 4.12-4.04 (m, 1H), 3.54 (ddd, J=14, 11, 5 Hz, 1H), 3.43 (s,3H), 2.98 (ddd, J=14, 11, 5 Hz, 1H), 2.90 (dd, J=14, 9 Hz, 1H),2.47-2.12 (m, 5H), 1.79-1.52 (m, 4H), 1.36-1.10 (m, 3H), 0.37-0.22 (m,4H).

EXAMPLE 2(d)(5R,15α,13E)-5-Methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.55 (Methanol:Chloroform=1:5); NMR: δ 7.40-7.10 (m, 4H), 5.78(dd, J=15.4, 5.6 Hz, 1H), 5.54 (dd, J=15.4, 8.4 Hz, 1H), 4.50-4.35 (m,1H), 4.41 (s, 2H), 4.10-3.98 (m, 1H), 3.60-3.45 (m, 1H), 3.42 (s, 3H),3.00-2.75 (m, 3H), 2.50-2.10 (m, 5H), 1.80-1.10 (m, 8H), 0.91 (d, J=5.8Hz, 3H).

EXAMPLE 2(e)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.38 (Methanol:Ethyl Acetate=1:10); NMR: δ 7.40-7.10 (m, 4H),5.75 (dd, J=15.6, 5.6 Hz, 1H), 5.52 (dd, J=15.6, 8.4 Hz, 1H), 4.67 (s,2H), 4.50-4.35 (m, 1H), 4.10-3.98 (m, 1H), 3.86 (q, J=8.8 Hz, 2H),3.60-3.35 (m, 1H), 3.00-1.80 (m, 6H), 2.33 (t, J=7.0 Hz, 2H), 1.80-1.55(m, 3H), 1.55-1.10 (m, 6H).

EXAMPLE 2(f)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.36 (Methanol:Ethyl Acetate=1:10); NMR: δ 7.35-7.15 (m, 3H),7.15-7.00 (m, 1H), 5.72 (dd, J=15.8, 5.8 Hz, 1H), 5.48 (dd, J=15.8, 8.2Hz, 1H), 4.42 (q, J=6.6 Hz, 1H), 4.10-3.98 (m, 1H), 3.60-3.40 (m, 1H),2.83 (d, J=6.6 Hz, 2H), 3.00-2.10 (m, 4H), 2.34 (t, J=7.2 Hz, 2H),1.80-1.55 (m, 3H), 1.55-1.10 (m, 6H).

EXAMPLE 2(g)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-2,3,4,17,18,19,20-heptanor-1,5-(2,5-interthienylene)-8-azaprost-13-enoicacid

TLC: Rf 0.22 (Chloroform:Methanol=9:1); NMR: δ 7.63 (d, J=3 Hz, 1H),7.33-7.25 (m, 2H), 7.19 (d, J=8 Hz, 1H), 7.13 (d, J=8 Hz, 1H), 6.81 (d,J=3 Hz, 1H), 5.73 (dd, J=15, 5 Hz, 1H), 5.50 (dd, J=15, 9 Hz, 1H), 4.52(d, J=11 Hz, 1H), 4.45 (d, J=11 Hz, 1H), 4.40-4.30 (m, 1H), 4.2-3.0(br), 4.02 (q, J=9 Hz, 1H), 3.46 (s, 3H), 3.50-3.35 (m, 1H), 2.98-2.68(m, 5H), 2.50-2.10 (m, 3H), 2.00-1.68 (m, 3H).

EXAMPLE 2(h)(15α,13E)-9-Oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.32 (Chloroform:Methanol=9: 1); NMR: δ 7.60-7.37 (m, 8H),7.24-7.17 (d, J=8.2 Hz, 1H), 5.74 (dd, J=15.0, 6.0 Hz, 1H), 5.49 (ddd,J=15.0, 8.6, 1.2 Hz, 1H), 4.51-4.40 (m, 1H), 4.08-3.99 (m, 1H),3.50-3.39 (m, 1H), 2.91 (d, J=6.6 Hz, 2H), 2.78-2.64 (m, 1H), 2.42-2.05(m, 6H), 1.77-1.51 (m, 3H), 1.42-1.06 (m, 6H).

EXAMPLE 2(i)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.34 (Chloroform:Methanol=10:1); NMR: δ 7.22-7.17 (m, 1H),7.07-6.98 (m, 3H), 5.74 (dd, J=15.3, 5.7 Hz, 1H), 5.50 (ddd, J=15.3,8.4, 1.2 Hz, 1H), 4.41 (m, 1H), 4.03 (m, 1H), 3.47 (m, 1H), 2.90-2.70(m, 3H), 2.40-2.10 (m, 6H), 2.33 (s, 3H), 1.76-1.22 (m, 9H).

EXAMPLE 2(j)(15α,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.30 (Chloroform:Methanol=10:1); NMR: δ 7.32-7.23 (m, 1H),6.99-6.90 (m, 3H), 5.72 (dd, J=15.3, 6.0 Hz, 1H), 5.50 (ddd, J=15.3,8.4, 1.2 Hz, 1H), 4.42 (m, 1H), 4.03 (m, 1H), 3.46 (m, 1H), 2.85 (d,J=6.0 Hz, 2H), 2.70 (m, 1H), 2.40-2.10 (m, 6H), 1.75-1.20 (m, 9H).

EXAMPLE 2(k)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.47 (Chloroform:Methanol: Water=9:1:0.1); NMR: δ 7.16 (m, 2H),7.00 (m, 2H), 5.72 (dd, J=15.4, 6.0 Hz, 1H), 5.49 (dd, J=15.4, 8.2 Hz,1H), 4.38 (m, 1H), 4.03 (m, 1H), 3.47 (m, 1H), 2.82 (d, J=6.6 Hz, 2H),2.72 (m, 1H), 2.41-2.31 (m, 2H), 2.34 (t, J=7.2 Hz, 2H), 2.21 (m, 1H),1.67 (m, 1H), 1.66-1.58 (m, 2H), 1.50-1.20 (m, 6H).

EXAMPLE 2(l)(15α,13E)-9-Oxo-15-hydroxy-16-(4-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.26 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.12 (d, J=8.2Hz, 2H), 7.07 (d, J=8.2 Hz, 2H), 5.73 (dd, J=15.4, 5.8 Hz, 1H), 5.47(dd, J=15.4, 8.8 Hz, 1H), 4.38 (m, 1H), 4.03 (m, 1H), 3.46 (m, 1H), 2.81(d, J=6.9 Hz, 2H), 2.72 (m, 1H), 2.40-2.27 (m, 4H), 2.34 (s, 3H), 2.21(m, 1H), 1.72 (m, 1H), 1.67-1.58 (m, 2H), 1.50-1.18 (m, 6H).

EXAMPLE 2(m)(15α,13E)-9-Oxo-15-hydroxy-16-(2-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.27 (Chloroform:Methanol=8:1); NMR: δ 7.28-7.00 (m, 4H), 5.76(dd, J=15.2, 6.0 Hz, 1H), 5.49 (ddd, J=15.2, 8.4, 0.6 Hz, 1H), 4.42 (m,1H), 4.04 (m, 1H), 3.46 (m, 1H), 2.87 (d, J=7.0 Hz, 2H), 2.72 (m, 1H),2.50-2.04 (m, 6H), 2.34 (s, 3H), 1.85-1.10 (m, 9H).

EXAMPLE 2(n)(15α,13E)-9-Oxo-15-hydroxy-16-(2-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.27 (Chloroform:Methanol=8:1); NMR: δ 7.34-6.94 (m, 4H), 5.74(dd, J=15.2, 6.0 Hz, 1H), 5.45 (ddd, J=15.2, 8.4, 0.8 Hz, 1H), 4.47 (m,1H), 4.02 (m, 1H), 3.44 (m, 1H), 3.40-1.90 (m, 9H), 1.80-0.90 (m, 9H).

EXAMPLE 2(o)(15α,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.18 (Chloroform:Methanol=8:1); NMR: δ 7.60-7.35 (m, 4H), 5.73(dd, J=15.3, 5.9 Hz, 1H), 5.50 (ddd, J=15.3, 8.3, 0.9 Hz, 1H), 4.46 (m,1H), 4.03 (m, 1H), 4.00-3.00 (br, 2H), 3.46 (m, 1H), 2.91 (d, J=6.3 Hz,2H), 2.71 (m, 1H), 2.48-2.06 (m, 5H), 1.76-1.12 (m, 9H).

EXAMPLE 2(p)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.16 (Chloroform:Methanol=8:1); NMR: δ 7.23 (dd, J=7.8, 7.8 Hz,1H), 6.86-6.70 (m, 3H), 5.73 (dd, J=15.3, 6.0 Hz, 1H), 5.48 (dd, J=15.3,8.4 Hz, 1H), 4.41 (m, 1H), 4.03 (m, 1H), 3.80 (s, 3H), 3.46 (m, 1H),2.82 (d, J=6.6 Hz, 2H), 2.71 (m, 1H), 2.50-2.04 (m, 5H), 1.80-1.10 (m,10H).

EXAMPLE 2(q)(15α,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.25 (Chloroform:Methanol: Water=9:1:0.1); NMR: δ 7.24 (t, J=7.3Hz, 1H), 7.11-6.97 (m, 3H), 5.74 (dd, J=15.1, 5.9 Hz, 1H), 5.50 (ddd,J=15.1, 8.3, 1.0 Hz, 1H), 4.42 (m, 1H), 4.04 (m, 1H), 3.45 (m, 1H),2.84-2.80 (m, 2H), 2.75 (m, 1H), 2.63 (q, J=7.8 Hz, 2H), 2.43-2.32 (m,2H), 2.35 (t, J=7.3 Hz, 2H), 2.21 (m, 1H), 1.71 (m, 1H), 1.68-1.57 (m,2H), 1.54-1.20 (m, 6H), 1.24 (t, J=7.8Hz, 3H)

EXAMPLE 2(r)(15α,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.30 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.14-7.00 (m,3H), 6.92 (m, 1H), 5.71 (dd, J=15.4, 5.8 Hz, 1H), 5.50 (dd, J=15.4, 8.6Hz, 1H), 4.38 (m, 1H), 4.04 (m, 1H), 3.44 (m, 1H), 2.82 (d, J=6.6 Hz,2H), 2.73 (m, 1H), 2.43-2.32 (m, 2H), 2.34 (t, J=7.1 Hz, 2H), 2.22 (m,1H), 1.69 (m, 1H), 1.65-1.55 (m, 2H), 1.51-1.20 (m, 6H).

EXAMPLE 2(s)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chloro-4-hydroxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.26 (Chloroform:Methanol=9:1); NMR: δ 7.14 (d, J=2.1 Hz, 1H),6.94 (dd, J=8.4, 2.1 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.65 (dd, J=15,6.3 Hz, 1H), 5.41 (ddd, J=15, 8.0, 1.2 Hz, 1H), 4.33 (m, 1H), 4.01 (m,1H), 3.41 (m, 1H), 2.85-2.62 (m, 3H), 2.57-2.10 (m, 8H), 1.79-1.56 (m,3H), 1.54-1.19 (m, 6H).

The hydroxyl group bound benzene ring was protected by THP group, andwas removed protecting group by acid before hydrolysis of the ester(procedure of Example 2)

EXAMPLE 2(t)(15α,13E)-9-Oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.34 (Chloroform:Methanol=9:1); NMR: δ 6.80-6.65 (m, 3H), 5.71(dd, J=15, 5.7 Hz, 1H), 5.50 (dd, J=15, 8.7 Hz, 1H), 4.41 (m, 1H), 4.03(m, 1H), 3.48 (m, 1H), 3.10-2.50 (m, 4H), 2.47-2.10 (m, 6H), 1.79-1.59(m, 3H), 1.58-1.20 (m, 6H).

EXAMPLE 2(u)(15α,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.26 (Chloroform:Methanol=10:1); NMR: δ 7.25-7.19 (m, 1H),7.08-7.00 (m, 3H), 5.75 (dd, J=15.3, 5.7 Hz, 1H), 5.51 (ddd, J=15.3,8.4, 0.9 Hz, 1H), 4.41 (m, 1H), 4.05 (m, 1H), 3.48 (m, 1H), 2.90-2.70(m, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.50-2.10 (m, 5H), 1.80-1.20 (m, 11H),0.94 (t, J=7.2 Hz, 3H).

EXAMPLE 2(v)(15α,13E)-9-Oxo-15-hydroxy-16-((E)-1-propenylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.30 (Chloroform:Methanol=10:1); NMR: δ 7.23-7.21 (m, 2H), 7.14(s, 1H), 7.02 (m, 1H), 6.37 (dd, J=15.6, 1.5 Hz, 1H), 6.27 (dq, J=15.6,6.3 Hz, 1H), 5.74 (dd, J=15.3, 6.0 Hz, 1H), 5.49 (ddd, J=15.3, 8.4, 1.2Hz, 1H), 4.41 (m, 1H), 4.02 (m, 1H), 3.45 (m, 1H), 2.83 (d, J=6.9 Hz,2H), 2.70 (m, 1H), 2.40-2.10 (m, 5H), 1.88 (dd, J=6.3, 1.5 Hz, 3H),1.80-1.20 (m, 9H).

EXAMPLE 2(w)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(2-fluorophenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.27 (Chloroform:Methanol=8:1); NMR:δ 7.60-6.80 (m, 8H), 5.72(m, 1H), 5.48 (m, 1H), 5.00-3.00 (br, 2H), 4.43 (m, 1H), 4.01 (m, 1H),3.43 (m, 1H), 2.98-2.60 (m, 3H), 2.48-2.00 (m, 5H), 1.98-0.88 (m, 9H).

EXAMPLE 2(x)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(4-fluorophenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.27 (Chloroform:Methanol=8:1); NMR: δ 7.64-7.00 (m, 8H), 5.72(m, 1H), 5.48 (m, 1H), 4.60-3.00 (br, 2H), 4.45 (m, 1H), 4.02 (m, 1H),3.44 (m, 1H), 2.96-2.60 (m, 3H), 2.48-2.02 (m, 5H), 1.78-0.78 (m, 9H).

EXAMPLE 2(y)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(5-methylfuran-2-yl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.25 (Chloroform:Methanol=8:1); NMR: δ 7.60-6.96 (m, 4H), 6.53(d, J=3.0 Hz, 1H), 6.05 (m, 1H), 5.72 (m, 1H), 5.48 (m, 1H), 4.60-2.80(br, 2H), 4.44 (m, 1H), 4.02 (m, 1H), 3.44 (m, 1H), 2.96-2.60 (m, 3H),2.48-2.02 (m, 8H), 1.80-1.06 (m, 9H).

EXAMPLE 2(z)(15α,13E)-9-Oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.83-7.76 (m,3H), 7.65 (s, 1H), 7.51-7.41 (m, 2H), 7.33 (dd, J=8.5, 1.7 Hz, 1H), 5.77(dd, J=15.4, 6.1 Hz, 1H), 5.44 (ddd, J=15.4, 8.5, 0.8 Hz, 1H), 4.54 (m,1H), 4.01 (m, 1H), 3.38 (m, 1H), 3.02 (d, J=6.9 Hz, 2H), 2.63 (m, 1H),2.37-2.32 (m, 2H), 2.34 (t, J=7.2 Hz, 2H), 2.19 (m, 1H), 1.64 (m, 1H),1.63-1.55 (m, 2H), 1.40-1.12 (m, 6H).

EXAMPLE 2(aa)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(2-methoxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.23 (Chloroform:Methanol=8:1); NMR: δ 7.50-6.92 (m, 8H), 5.74(m, 1H), 5.50 (m, 1H), 4.43 (m, 1H), 4.03 (m, 1H), 3.81 (s, 3H), 3.45(m, 1H), 3.40-1.90 (br, 2H), 3.00-2.64 (m, 3H), 2.48-2.14 (m, 5H),1.78-1.10 (m, 9H).

EXAMPLE 2(bb)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(2-hydroxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.26 (Chloroform:Methanol=8:1); NMR: δ 7.46-7.08 (m, 7H), 6.97(m, 1H), 5.72 (m, 1H), 5.47 (m, 1H), 4.42 (m, 1H), 4.02 (m, 4.02 (m 1H),3.43 (m, 1H), 2.98-2.62 (m, 3H), 2.50-2.06 (m, 5H), 1.80-1.08 (m, 9H).

The hydroxyl group bound benzene ring was protected by THP group, andwas removed protecting group by acid before hydrolysis of the ester(procedure of Example 2)

EXAMPLE 2(cc)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(3-hydroxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.21 (Chloroform:Methanol=8:1); NMR: δ 7.48-6.80 (m, 8H), 5.70(dd, J=15.3, 6.3 Hz, 1H), 5.51 (m, 1H), 4.44 (m, 1H), 4.06 (m, 1H), 3.49(m, 1H), 3.06-2.60 (m, 3H), 2.54-1.96 (m, 5H), 1.82-1.00 (m, 9H).

The hydroxyl group bound benzene ring was protected by THP group, andwas removed protecting group at final step.

EXAMPLE 2(dd)(15α,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoicacid

TLC: Rf 0.20 (Chloroform:Methanol=10:1); NMR: δ 7.68 (d, J=3.6 Hz, 1H),7.23-7.18 (m, 3H), 7.08 (m, 1H), 6.83 (d, J=3.6 Hz, 1H), 5.71 (dd,J=15.3, 6.0 Hz, 1H), 5.48 (ddd, J=15.3, 8.7, 0.9 Hz, 1H), 4.39 (m, 1H),4.02 (m, 1H), 3.53 (m, 1H), 3.40 (br s, 1H), 2.90-2.70 (m, 5H),2.50-2.10 (m, 3H), 1.90-1.60 (m, 3H).

EXAMPLE 2(ee)(15α,13E)-9-Oxo-15-hydroxy-16-(3-cyclopropylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.19 (t, J=7.7Hz, 1H), 7.02-6.89 (m, 3H), 5.73 (dd, J=15.4, 5.8 Hz, 1H), 5.48 (ddd,J=15.4, 8.5, 1.0 Hz, 1H), 4.42 (m, 1H), 4.04 (m, 1H), 3.45 (m, 1H), 2.81(d, J=6.6 Hz, 2H), 2.75 (m, 1H), 2.43-2.30 (m, 2H), 2.32 (t, J=7.1 Hz,2H), 2.21 (m, 1H), 1.86 (m, 1H), 1.71 (m, 1H), 1.67-1.56 (m, 2H),1.52-1.19 (m, 6H), 1.00-0.90 (m, 2H), 0.74-0.63 (m, 2H).

EXAMPLE 2(ff)(13E)-9-Oxo-15-hydroxy-16,16-difluoro-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.34 (Chloroform:Methanol=9:1); NMR: δ 7.57-7.35 (m, 4H),5.78-5.59 (m, 2H), 4.61-4.43 (m, 3H), 4.04 (m, 1H), 3.50-3.32 (m, 4H),2.82 (m, 1H), 2.43-2.10 (m, 5H), 1.72-1.20 (m, 9H).

EXAMPLE 2(gg)(15α,13E)-9-Oxo-15-hydroxy-16-(3-ethoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.48 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.22 (t, J=7.7Hz, 1H), 6.81-6.73 (m, 3H), 5.73 (dd, J=15.4, 6.1 Hz, 1H), 5.48 (ddd,J=15.4, 8.5, 1.1 Hz, 1H), 4.41 (m, 1H), 4.03 (m, 1H), 4.02 (q, J=7.1Hz,2H), 3.45 (m, 1H), 2.81 (d, J=6.6 Hz, 2H), 2.72 (m, 1H), 2.42-2.32 (m,4H), 2.21 (m, 1H), 1.76-1.58 (m, 3H), 1.48-1.20 (m, 6H), 1.42 (t, J=7.1Hz, 3H).

EXAMPLE 2(hh)(15α,13E)-9-Oxo-15-hydroxy-16-(3-isopropyloxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.20 (t, J=7.7Hz, 1H), 6.80-6.75 (m, 3H), 5.73 (dd, J=15.4, 6.0 Hz), 1H), 5.49 (ddd,J=15.4, 8.5, 1.1 Hz, 1H), 4.55 (m, 1H), 4.40 (m, 1H), 4.04 (m, 1H), 3.54(m, 1H), 2.80 (d, J=6.6 Hz, 2H), 2.74 (m, 1H), 2.42-2.32 (m, 4H), 2.21(m, 1H), 1.77-1.58 (m, 3H), 1.50-1.20 (m, 6H), 1.38 (d, J=6.0 Hz, 6H).

EXAMPLE 2(ii)(15α,13E)-9-Oxo-15-hydroxy-16-(3-benzyloxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.49 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.45-7.28 (m,5H), 7.23 (t, J=7.7 Hz, 1H), 6.89-6.76 (m, 3H), 5.71 (dd, J=15.4, 6.0Hz, 1H), 5.45 (ddd, J=15.4, 8.5, 0.8 Hz, 1H), 5.03 (s, 2H), 4.39 (m,1H), 4.01 (m, 1H), 3.45 (m, 1H), 2.81 (d, J=6.9 Hz, 2H), 2.71 (m, 1H),2.41-2.27 (m, 4H), 2.20 (m, 1H), 1.75-1.54 (m, 3H), 1.48-1.20 (m, 6H).

EXAMPLE 2(jj)(15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoicacid

TLC: Rf 0.31 (Chloroform:Methanol=9:1); NMR: δ 7.32-7.11 (m, 4H), 5.70(dd, J=16, 5 Hz, 1H), 5.60-5.48 (m, 2H), 5.34-5.25 (m, 1H), 4.44 (s,2H), 4.50-4.39 (m, 1H), 4.20 (dd, J=15, 5 Hz, 1H), 4.03 (dt, J=8, 5 Hz,1H), 3.49 (dd, J=15, 8 Hz, 1H), 3.42 (s, 3H), 2.92-2.78 (m, 2H),2.50-2.05 (m, 7H), 1.77-1.61 (m, 3H).

EXAMPLE 2(kk)(15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoicacid

TLC: Rf 0.27 (Chloroform:Methanol=8:1); NMR: δ 7.62-7.26 (m, 4H), 5.67(dd, J=15.6, 5.7 Hz, 1H), 5.62-5.44 (m, 2H), 5.28 (m, 1H), 4.45 (m, 1H),4.21 (dd, J=15.0, 6.6 Hz, 1H), 4.03 (m, 1H), 3.80-2.40 (br, 2H), 3.45(m, 1H), 2.90 (d, J=6.6 Hz, 2H), 2.48-2.02 (m, 7H), 1.76-1.52 (m, 3H).

EXAMPLE 2(ll)(15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoicacid

TLC: Rf 0.32 (Chloroform:Methanol=8:1); NMR: δ 7.19 (dd, J 1.5, 7.5 Hz,1H), 7.10-7.05 (m, 3H), 5.68 (dd, J=15.6, 5.7 Hz, 1H), 5.61-5.40 (m,2H), 5.30 (m, 1H), 4.41 (m, 1H), 4.21 (m, 1H), 4.03 (m, 1H), 3.70-2.60(br, 2H), 3.44 (m, 1H), 2.80 (d, J=6.6 Hz, 2H), 2.48-2.04 (m, 10H),1.78-1.56 (m, 3H).

EXAMPLE 2(mm)(15α,13E)-9-Oxo-15-hydroxy-16-(3,5-dimethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.36 (Chloroform:Methanol=10:1); NMR: δ 6.88 (s, 1H), 6.81 (s,2H), 5.74 (dd, J=15.3, 5.7 Hz, 1H), 5.51 (dd, J=15.3, 8.4 Hz, 1H), 4.39(m, 1H), 4.04 (m, 1H), 3.48 (m, 1H), 2.83-2.69 (m, 3H), 2.50-2.10 (m,5H), 2.29 (s, 6H), 1.80-1.20 (m, 9H).

EXAMPLE 2(nn)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.26 (Chloroform:Methanol=10:1); NMR: δ 7.74-7.72 (m, 2H),7.59-7.50 (m, 2H), 7.39 (m, 1H), 7.32-7.18 (m, 3H), 7.03 (d, J=1.2 Hz,1H), 5.77 (dd, J=15.3, 6.3 Hz, 1H), 5.51 (ddd, J=15.3, 8.7, 0.9 Hz, 1H),4.48 (m, 1H), 4.03 (m, 1H), 3.43 (m, 1H), 2.93 (d, J=6.6 Hz, 2H),2.69(m, 1H), 2.45-2.10 (m, 5H), 1.75-1.10 (m, 9H).

EXAMPLE 2(oo)(15α,13E)-2,7-(1,3-Interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf 0.42 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.27-6.97 (m,8H), 5.62 (dd, J=15.4, 5.8 Hz, 1H), 5.41 (ddd, J=15.4, 8.8, 1.1 Hz, 1H),4.74 (d, J=14.6 Hz, 1H), 4.36 (m, 1H), 3.87 (m, 1H), 3.81 (d, J=14.6 Hz,1H), 3.60 (s, 2H), 2.78 (d, J=6.6 Hz, 2H), 2.55-2.35 (m, 2H), 2.32 (s,3H), 2.15 (m, 1H), 1.69 (m, 1H).

EXAMPLE 2(pp)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(2-phenylethynyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.21 (Chloroform:Methanol=8:1); NMR: δ 7.60-7.14 (m, 9H), 5.72(dd, J=15.3, 6.0 Hz, 1H), 5.47 (dd, J=15.3, 8.4 Hz, 1H), 4.43 (m, 1H),4.03 (m, 1H), 3.46 (m, 1H), 2.94-2.62 (m, 3H), 2.48-2.12 (m, 5H),1.80-1.16 (m, 9H).

EXAMPLE 2(qq)(15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoicacid

TLC: Rf 0.31 (Chloroform:Methanol=8:1); NMR: δ 7.40-7.00 (m, 4H), 5.66(dd, J=15.6, 5.7 Hz, 1H), 5.61-5.22 (m, 3H), 4.41 (m, 1H), 4.22 (m, 1H),4.03 (m, 1H), 3.80-2.80 (br, 2H), 3.44 (m, 1H), 2.90-2.70 (m, 3H),2.48-2.02 (m, 6H), 1.76-1.54 (m, 3H).

EXAMPLE 2(rr)(15α,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoicacid

TLC: Rf 0.24 (Chloroform:Methanol=8:1); NMR: δ 7.20-6.84 (m, 3H), 5.66(dd, J=15.3, 5.7 Hz, 1H), 5.62-5.22 (m, 3H), 4.38 (m, 1H), 4.21 (m, 1H),4.04 (m, 1H), 4.02-3.00 (br, 2H), 3.46 (m, 1H), 2.79 (d, J=6.6 Hz, 2H),2.50-2.02 (m, 7H), 1.80-1.54 (m, 3H).

EXAMPLE 2(ss)(15α,13E)-2,7-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf 0.25 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.24-6.96 (m,8H), 5.62 (dd, J=15.4, 6.0 Hz, 1H), 5.43 (ddd, J=15.4, 8.2, 0.8Hz, 1H),4.78 (d, J=14.8 Hz, 1H), 4.37 (m, 1H), 3.89 (m, 1H), 3.77 (d, J=14.8 Hz,1H), 3.62 (s, 2H), 2.80 (d, J=6.6 Hz, 2H), 2.55-2.37 (m, 2H), 2.36 (s,3H), 2.15 (m, 1H), 1.74 (m, 1H).

EXAMPLE 2(tt)(15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoicacid

TLC: Rf 0.28 (Chloroform:Methanol=8:1); NMR: δ 7.25 (m, 1H), 7.04-6.86(m, 3H), 5.66 (dd, J=15.3, 5.7 Hz, 1H), 5.60-5.20 (m, 3H), 4.42 (m, 1H),4.40-2.80 (br, 2H), 4.21 (m, 1H), 4.03 (m, 1H), 3.44 (m, 1H), 2.90-2.72(m, 2H), 2.48-2.02 (m, 7H), 1.78-1.56 (m, 3H).

EXAMPLE 2(uu)(15α,5Z,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoicacid

TLC: Rf 0.28 (Chloroform:Methanol=8:1); NMR: δ 7.22-7.10 (m, 2H),7.05-6.93 (m, 2H), 5.66 (dd, J=15.6, 5.7 Hz, 1H), 5.61-5.20 (m, 3H),4.70-3.20 (br, 2H), 4.38 (m, 1H), 4.20 (m, 1H), 4.02 (m, 1H), 3.44 (m,1H), 2.81 (d, J=6.6 Hz, 2H), 2.48-2.02 (m, 7H), 1.78-1.56 (m, 3H).

EXAMPLE 2(vv)(15α,5Z,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-2,6-(1,3-interphenylene)-3,4,5,17,18,19,20-heptanor-8-azaprost-13-enoicacid

TLC: Rf 0.30 (Chloroform:Methanol=9:1); NMR: δ 7.25-7.0 (m, 8H), 5.51(dd, J=15, 6 Hz, 1H), 5.25 (dd, J=15, 8 Hz, 1H), 4.4-4.3 (m, 1H),3.75-3.65 (m, 1H), 3.62 (s, 2H), 3.65-3.55 (m, 1H), 3.3-2.4 (br),3.0-2.7 (m, 5H), 2.4-2.2 (m, 2H), 2.1-1.95 (m, 1H), 1.65-1.5 (m, 1H).

EXAMPLE 2(ww)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoicacid

TLC: Rf 0.31 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.68 (d, J=3.8Hz, 1H), 7.19 (t, J=7.4 Hz, 1H), 7.07-6.96 (m, 3H), 6.83 (d, J=3.8 Hz,1H), 5.75 (dd, J=15.4, 6.0 Hz, 1H), 5.47 (ddd, J=15.4, 8.8, 1.1 Hz, 1H),4.38 (m, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 2.90-2.76 (m, 5H), 2.46-2.37(m, 2H), 2.33 (s, 3H), 2.21 (m, 1H), 1.90-1.65 (m, 3H).

EXAMPLE 2(xx)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxadiazol-3yl)thiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene

TLC: Rf 0.24 (Chloroform:Methanol=9:1); NMR(DMSO-d₆): δ 12.98 (br. s,1H), 7.52 (d, J=4.0 Hz, 1H), 7.22-7.14 (m, 2H), 7.08-6.99 (m, 3H), 5.62(dd, J=15.0, 6.2 Hz, 1H), 5.30 (dd, J=15.0, 8.8 Hz, 1H), 4.97 (br. s,1H), 4.16 (m, 1H), 4.00 (m, 1H), 3.28 (m, 2H), 2.81-2.58 (m, 4H),2.22-2.03 (m, 3H), 1.77-1.50 (m, 3H).

Hydrolysis of the ester (procedure of Example 2) was not done. The NHgroup bound 1,2,4-oxadiazole ring was protected by Boc group, and wasremoved protecting group at final step.

EXAMPLE 2(yy)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interfurylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoicacid

TLC: Rf 0.25 (Chloroform:Methanol=2:1); NMR: δ 7.20-7.14 (m, 3H),7.04-6.94 (m, 2H), 6.21 (d, J=3.6 Hz, 1H), 5.73 (dd, J=15.4, 5.8 Hz,1H), 5.49 (dd, J=15.4, 8.8 Hz, 1H), 5.14 (brs, 2H), 4.38 (m, 1H), 4.06(m, 1H), 3.51 (m, 1H), 2.86 (m, 1H), 2.81 (d, J=6.6 Hz, 2H), 2.66 (t,J=7.4 Hz, 2H), 2.48-2.29 (m, 2H), 2.18 (m, 1H), 1.93-1.80 (m, 2H), 1.72(m, 1H).

EXAMPLE 2(zz)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienylene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-enoicacid

TLC: Rf 0.48 (Chloroform:Methanol=9:1); NMR(CDCl₃+CD₃OD): δ 7.25-7.15(m, 2H), 7.05-6.95 (m, 2H), 6.7-6.6 (m, 2H), 5.72 (dd, J=16, 6 Hz, 1H),5.45 (dd, J=16, 8 Hz, 1H), 4.78 (d, J=15 Hz, 1H), 4.37 (q, J=6 Hz, 1H),4.05-3.95 (m, 1H), 3.90 (d, J=15 Hz, 1H), 3.09 (t, J=7 Hz, 2H), 2.83 (d,J=6 Hz, 2H), 2.65 (t, J=7 Hz, 2H), 2.5-2.25 (m, 2H), 2.25-2.1 (m, 1H),1.8-1.6 (m, 1H).

EXAMPLE 2(aaa)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(tetrazol-5-yl)thiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene

TLC: Rf 0.52 (Chloroform:Methanol=2:1); NMR(DMSO-d₆): δ 7.59 (d, J=3.7Hz, 1H), 7.21-7.13 (m, 2H), 7.08-6.99 (m, 3H), 5.62 (dd, J=15.4, 6.2 Hz,1H), 5.31 (dd, J=15.4, 8.8 Hz, 1H), 4.97 (br, 1H), 4.17 (m, 1H), 4.02(m, 1H), 3.33 (m, 1H), 2.82-2.58 (m, 5H), 2.27-2.03 (m, 3H), 1.80-1.49(m, 3H).

Hydrolysis of the ester (procedure of Example 2) was not done. The NHgroup bound 1,2,4-oxadiazole ring was protected by Boc group, and wasremoved protecting group at final step.

EXAMPLE 2(bbb)(15α,13E)-9-Oxo-15-hydroxy-16-(naphthalen-1-yl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

TLC: Rf 0.45 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 8.04 (m, 1H),7.87 (m, 1H), 7.76 (m, 1H), 7.57-7.46 (m, 2H), 7.44-7.32 (m, 2H), 5.78(dd, J=15.4, 6.1 Hz, 1H), 5.45 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.57 (m,1H), 3.97 (m, 1H), 3.35 (m, 1H), 3.32 (d, J=6.6 Hz, 2H), 2.64 (m, 1H),2.37-2.32 (m, 2H), 2.34 (t, J=7.1 Hz, 2H), 2.15 (m, 1H), 1.64-1.55 (m,3H), 1.43-1.15 (m, 6H).

REFERENCE EXAMPLE 62-((5R)-5-t-Butyldimethylsilyloxymethyl-2-oxopyrrolidin-1-yl)acetic acidmethyl ester

Under atmosphere of argon, a solution of potassium t-butoxide (11.58 g)in dry tetrahydrofuran (100 mL) was added to the solution of thecompound prepared in Reference Example 1 (21.41 g) in tetrahydrofuran(200 mL) on water bath. After the mixture was stirred for 1 hour, asolution of bromoacetic acid methyl ester (9.75 mL) in tetrahydrofuran(50 mL) was added hereto. Then hexane was added to the mixture. Thediluted solution was washed with water and brine successively, driedover an anhydrous sodium sulfate, concentrated under reduced pressureand was purified by column chromatography on silica gel (ethylacetate:hexane=from 1:2 to 1:1, then 3:1) to give the title compound(22.13 g) having the following physical data.

TLC: Rf 0.48 (Ethyl Acetate:Hexane=1:1).

REFERENCE EXAMPLE 72-((5R)-5-t-Butyldimethylsilyloxymethyl-2-oxopyrrolidin-1-yl)ethanol

To a solution of the compound prepared in Reference Example 6 (22.0 g)in tetrahydrofuran (100 mL), sodium borohydride (8.28 g) was added, andthe mixture was stirred for 5 minutes. Methanol (20 mL) was addedhereto, and the mixture was stirred for 15 minutes. Methanol (30 mL) wasadded hereto again, and the mixture was stirred for 1 hour. After waterwas added to the mixture, ethyl acetate was added hereto. The organiclayer was washed with water and brine successively, dried over ananhydrous sodium sulfate, concentrated under reduced pressure to givethe title compound (19.75 g) having the following physical data.

TLC: Rf 0.43 (Ethyl Acetate).

REFERENCE EXAMPLE 8(5R)-2-(5-t-Butyldimethylsilyloxymethyl-2-oxopyrrolidinyl)ethylthioacetate

Under atmosphere of argon, a mixture of the compound prepared inReference Example 7 (22.0 g), triethylamine (13.0 mL) and drytetrahydrofuran (150 mL) was dropped by mesyl chloride (6.7 mL) at −5°C., and the mixture was stirred for 45 minutes. After reaction wasterminated, methanol (0.81 mL) was added hereto, and the mixture wasstirred for 15 minutes. To the mixture, a mixture of pottasium carbonate(20.0 g), potassium thioacetate and dry dimethylformamide (150 mL) wasadded, and the mixture was stirred for 3 hours at 50° C., then for 2days at room temperature. Then mixed solvent of ethyl acetate and hexanewas added to the mixture. The diluted solution was washed with water andbrine successively, dried over an anhydrous sodium sulfate, concentratedunder reduced pressure to give the title compound (26.8 g) having thefollowing physical data.

TLC: Rf 0.83 (Ethyl Acetate).

REFERENCE EXAMPLE 99-Oxo-13-(t-butyldimethylsilyloxy)-14,15,16,17,18,19,20-heptanor-5-thia-8-azaprostanoicacid methyl ester

Under atmosphere of argon, a solution of the compound prepared inReference Example 8 (26.8 g) and 4-iodobutanoic acid methyl ester (19.9g) in dry methanol (150 mL) was added by pottasium carbonate (14.0 g),and the mixture was stirred for 2 hours. Then mixed solvent of diethylether and ethyl acetate was added to the mixture. The diluted solutionwas washed with 0.5N hydrochloric acid, water and brine successively,dried over an anhydrous sodium sulfate, concentrated under reducedpressure to give the title compound (31.28 g) having the followingphysical data.

TLC: Rf 0.67 (Ethyl Acetate:Hexane=1:1).

REFERENCE EXAMPLE 109-Oxo-13-hydroxy-14,15,16,17,18,19,20-heptanor-5-thia-8-azaprostanoicacid methyl ester

To a solution of the compound prepared in Reference Example 9 (31.28 g)in methanol (70 mL), p-toluenesulfonic acid monohydrate (2.41 g) wasadded, and the mixture was stirred for 4 hours at 50° C. It was cooledto room temperature, the mixture was added by triethylamine (1.95 mL),concentrated under reduced pressure and was purified by columnchromatography on silica gel (from ethyl acetate:hexane=1:1 to ethylacetate:methanol=100:1) to give the title compound (16.67 g) having thefollowing physical data.

TLC: Rf 0.14 (Ethyl Acetate).

REFERENCE EXAMPLE 119-Oxo-12-formyl-13,14,15,16,17,18,19,20-octanor-5-thia-8-azaprostanoicacid methyl ester

Under atmosphere of argon, a solution of the compound prepared inReference Example 10 (1.04 g) and diisopropylethylamine (3.8 mL) inmixed solvent of ethyl acetate (6 mL) and dimethylsulfoxide (6 mL) wasadded by sulfur trioxide pyridine complex (1.72 g) on ice bath, and themixture was stirred for 40 minutes. 0.5N hydrochloric acid was added tothe reaction mixture, then the mixture was extracted by chloroform. Theorganic layer was dried over an anhydrous sodium sulfate, concentratedunder reduced pressure to give the title compound (1.0 g) having thefollowing physical data.

TLC: Rf 0.50 (Chloroform:Methanol=9:1).

EXAMPLE 3(a) to EXAMPLE 3(rr)

By the same procedure as describe in Reference Example 5, Examples 1 and2 using the compound prepared in Reference Example 11 or correspondingaldehyde derivatives instead of the compound prepared in ReferenceExample 4, the compound of the present invention having the followingphysical data were obtained.

EXAMPLE 3(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.35 (Methanol:Chloroform=1:5); NMR: δ 7.40-7.10 (m, 4H), 5.79(dd, J=15.4, 5.2 Hz, 1H), 5.54 (dd, J=15.4, 8.4 Hz, 1H), 4.50-4.40 (m,1H), 4.46 (s, 2H), 4.20-4.05 (m, 1H), 3.70-3.50 (m, 1H), 3.42 (s, 3H),3.20-2.90 (m, 1H), 2.90-2.80 (m, 2H), 2.80-2.10 (m, 9H), 2.00-1.60 (m,3H).

EXAMPLE 3(b)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.45 (Methanol:Chloroform=1:5); NMR: δ 7.30-7.20 (m, 3H),7.20-7.05 (m, 1H), 5.75 (dd, J=15.4, 5.4 Hz, 1H), 5.49 (dd, J=15.4, 8.6Hz, 1H), 4.50-4.35 (m, 1H), 4.20-4.05 (m, 1H), 3.75-3.55 (m, 1H),3.10-2.85 (m, 1H), 2.85 (d, J=6.6 Hz, 2H), 2.80-2.10 (m, 9H), 2.00-1.80(m, 2H), 1.80-1.60 (m, 1H).

EXAMPLE 3(c)(15α,13E)-9-Oxo-15-hydroxy-16-(3-cyclopropyloxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.47 (Chloroform:Methanol=9:1); NMR: δ 7.37-7.11 (m, 4H), 5.80(dd, J=15, 5Hz, 1H), 5.55 (dd, J=15, 8Hz, 1H), 4.56 (s, 2H), 4.50-4.40(m, 1H), 4.17-4.08 (m, 1H), 3.63-3.51 (m, 1H), 3.42-3.36 (m, 1H),3.11-3.00 (m, 1H), 2.89 (dd, J=14, 6 Hz, 1H), 2.80 (dd, J=14, 8 Hz, 1H),2.72-2.32 (m, 8H), 2.31-2.17 (m, 1H), 1.98-1.83 (m, 2H), 1.79-1.65 (m,1H), 0.71-0.49 (m, 4H).

EXAMPLE 3(d)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.47 (Chloroform:Methanol=9:1); NMR: δ 7.38-7.14 (m, 4H), 5.77(dd, J=15, 6 Hz, 1H), 5.53 (dd, J=15, 8 Hz, 1H), 4.65 (s, 2H), 4.50-4.40(m, 1H), 4.18-4.08 (m, 1H), 3.86 (q, J=9 Hz, 2H), 3.68-3.55 (m, 1H),3.08-2.94 (m, 1H), 2.94-2.79 (m, 2H), 2.68-2.32 (m, 8H), 2.32-2.17 (m,1H), 1.98-1.82 (m, 2H), 1.78-1.63 (m, 1H).

EXAMPLE 3(e)(15α,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.50 (Methanol:Ethyl Acetate=1:5); NMR: δ 7.30-7.20 (m, 1H),7.10-7.00 (m, 3H), 5.78 (dd, J=15.4, 5.4 Hz, 1H), 5.52 (dd, J=15.4, 8.4Hz, 1H), 4.50-4.40 (m, 1H), 4.20-4.05 (m, 1H), 3.75-3.55 (m, 1H),3.20-2.10 (m, 14H), 2.00-1.80 (m, 2H), 1.80-1.55 (m, 3H), 0.94 (t, J=7.2Hz, 3H).

EXAMPLE 3(f)(15α,13E)-9-Oxo-15-hydroxy-16-cyclopentyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.26 (Chloroform:Methanol=9:1); NMR: δ 5.75 (dd, J=15.3, 6.0 Hz,1H), 5.53 (ddd, J=15.3, 8.0, 1.0 Hz, 1H), 4.29-4.10 (m, 2H), 3.77-3.60(m, 1H), 3.20-3.08 (m, 1H), 2.79-1.43 (m, 22H), 1.22-1.04 (m, 2H).

EXAMPLE 3(g)(15α,13E)-9-Oxo-15-hydroxy-16-(thiophen-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-12-enoicacid

TLC: Rf 0.18 (Chloroform:Methanol=9:1); NMR: δ 7.19 (d, J=5.1 Hz, 1H),6.95 (dd, J=5.1, 3.3 Hz, 1H), 6.86 (d, J=3.3 Hz, Hz, 1H), 5.75 (dd,J=15.0, 5.4 Hz, 1H), 5.55 (dd, J=15.0, 8.6 Hz, 1H), 4.48-4.39 (m, 1H),4.19-4.06 (m, 1H), 3.70-3.59 (m, 1H), 3.42-2.75 (m, 4H), 2.70-2.18 (m,10H), 1.99-1.99-1.84 (m, 2H), 1.79-1.62 (m, 1H).

EXAMPLE 3(h)(15α,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.40 (Chloroform:Methanol=9:1); NMR: δ 7.59-7.38 (m, 4H),5.82-5.71 (m, 1H), 5.60-5.41 (m, 1H), 4.57-4.40 (m, 1H), 4.20-4.06 (m,1H), 3.70-3.59 (m, 1H), 3.15-2.81 (m, 3H), 2.80-2.01 (m, 10H), 1.99-1.80(m, 2H), 1.79-1.60 (m, 1H).

EXAMPLE 3(i)(15α,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.40 (Chloroform:Methanol=10:1); NMR: δ 7.32-7.19 (m, 5H), 5.77(dd, J=15.3, 5.4 Hz, 1H), 5.51 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.41 (m,1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.95 (m, 1H), 2.86 (d, J=6.6 Hz, 2H),2.65-2.20 (m, 9H), 2.00-1.80 (m, 2H), 1.70 (m, 1H).

EXAMPLE 3(i)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.32 (Chloroform:Methanol=10:1); NMR: δ 7.21 (m, 1H), 7.07-6.98(m, 3H), 5.78 (dd, J=15.3, 5.4 Hz, 1H), 5.52 (ddd, J=15.3, 8.7, 1.2 Hz,1H), 4.43 (m, 1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.95 (m, 1H), 2.83-2.20(m, 11H), 2.34 (S, 3H), 2.00-1.80 (m, 2H), 1.70 (m, 1H).

EXAMPLE 3(k)(15α,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.38 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.27 (m, 1H),7.00-6.89 (m, 3H), 5.75 (dd, J=15.4, 5.5 Hz, 1H), 5.50 (dd, J=15.4, 8.5Hz, 1H), 4.42 (m, 1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.92 (m, 1H), 2.84(d, J=6.9 Hz, 2H), 2.67-2.51 (m, 4H), 2.50-2.41 (m, 2H), 2.38 (t, J=7.1Hz, 2H), 2.22 (m, 1H), 1.94-1.83 (m, 2H), 1.66 (m, 1H).

EXAMPLE 3(l)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.38 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.20-7.16 (m,2H), 7.04-6.96 (m, 2H), 5.75 (dd, J=15.4, 6.0 Hz, 1H), 5.50 (ddd,J=15.4, 8.5, 1.1 Hz, 1H), 4.39 (m, 1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.95(m, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.67-2.53 (m, 4H), 2.52-2.43 (m, 2H),2.39 (t, J=7.1 Hz, 2H), 2.22 (m, 1H), 1.94-1.83 (m, 2H), 1.68 (m, 1H).

EXAMPLE 3(m)(15α,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.24 (Chloroform:Methanol=10:1); NMR: δ 7.14-7.00 (m, 2H), 6.92(m, 1H), 5.76 (dd, J=15.6, 5.4 Hz, 1H), 5.54 (ddd, J=15.6,8.4, 1.2 Hz,1H), 4.40 (m, 1H), 4.12 (m, 1H), 3.63 (m, 1H), 3.00 (m, 1H), 2.82-2.10(m, 11H), 2.00-1.60 (m, 3H).

EXAMPLE 3(n)(15α,13E)-9-Oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.27 (Chloroform:Methanol=10:1); NMR: δ 7.82-7.77 (m, 3H), 7.65(s, 1H), 7.50-7.40 (m, 2H), 7.32 (dd, J=8.4, 1.5 Hz, 1H), 5.80 (dd,J=15.6, 5.1 Hz, 1H), 5.51 (ddd, J=15.6, 8.4, 1.2 Hz, 1H), 4.53 (m, 1H),4.11 (m, 1H), 3.53 (m, 1H), 3.02 (d, J=6.6 Hz, 2H), 2.86 (m, 1H),2.60-2.10 (m, 9H), 2.00-1.60 (m, 3H).

EXAMPLE 3(o)(15α,13E)-2,3-Methano-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.37 (Chloroform:Methanol=10:1); NMR: δ 7.26-7.19 (m, 3H), 7.09(m, 1H), 5.73 (dd, J=15.3, 5.7 Hz, 1H), 5.48 (m, 1H), 4.41 (m, 1H), 4.12(m, 1H), 3.62 (m, 1H), 3.05-2.20 (m, 9H), 2.83 (d, J=6.3 Hz, 2H),1.80-1.60 (m, 2H), 1.34 (m, 1H), 0.90 (m, 1H).

EXAMPLE 3(p)(15α,13E)-9-Oxo-15-hydroxy-16-(3-t-butylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.43 (Chloroform:Methanol=9:1); NMR: δ 7.38-7.20 (m, 3H),7.06-6.99 (m, 1H), 5.79 (dd, J=15.3, 5.4 Hz, 1H), 5.54 (dd, J=15.3, 8.4Hz, 1H), 4.43 (m, 1H), 4.12 (m, 1H), 3.62 (m, 1H), 3.37-2.20 (m, 14H),1.99-1.83 (m, 2H), 1.73 (m, 1H), 1.31 (s, 9H).

EXAMPLE 3(q)(13E)-9-Oxo-15-hydroxy-16α-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid

TLC: Rf 0.32 (Chloroform:Methanol=8:1); NMR: δ 7.40-7.12 (m, 5H), 5.58(dd, J=15.3, 6.3 Hz, 1H), 5.36 (ddd, J=15.3, 8.4, 0.9 Hz, 1H), 4.26 (m,1H), 4.02 (m, 1H), 3.90-2.80 (br, 2H), 3.52 (m, 1H), 2.85 (m, 1H), 2.66(m, 1H), 2.60-2.06 (m, 9H), 1.98-1.80 (m, 2H), 1.61 (m, 1H), 1.35 (d,J=7.2 Hz, 3H).

Stereochemistry at C15 position is not determined, but this compound isa single isomer.

EXAMPLE 3(r)(13E)-9-Oxo-15-hydroxy-16β-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.25 (Chloroform:Methanol=8:1); NMR: δ 7.42-7.14 (m, 5H), 5.73(dd, J=15.3, 6.3 Hz, 1H), 5.55 (dd, J=15.3, 8.1 Hz, 1H), 4.24 (dd,J=6.6, 6.3 Hz, 1H), 4.15 (m, 1H), 3.71 (m, 1H), 3.60-2.70 (br, 2H), 3.06(m, 1H), 2.84 (m, 1H), 2.76-2.14 (m, 9H), 2.00-1.82 (m, 2H), 1.71 (m,1H), 1.27 (d, J=7.2 Hz, 3H).

Stereochemistry at C15 position is not determined, but this compound isa single isomer.

EXAMPLE 3(s)(15α,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.49 (Chloroform:Methanol=9:1); NMR: δ 7.24 (m, 1H), 7.13-6.98(m, 3H), 5.78 (dd, J=15.4, 5.5 Hz, 1H), 5.52 (ddd, J=15.4, 8.2, 1.1 Hz,1H), 4.42 (m, 1H), 4.12 (m, 1H), 3.63 (m, 1H), 3.00 (m, 1H), 2.90-2.77(m, 2H), 2.67-2.35 (m, 10H), 2.23 (m, 1H), 1.95-1.85 (m, 2H), 1.72 (m,1H), 1.22 (t, J=7.4 Hz, 3H).

EXAMPLE 3(t)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.35 (Chloroform:Methanol=8:1); NMR: δ 7.52-7.35 (m, 2H), 7.14(dd, J=9.3, 9.3 Hz, 1H), 5.77 (dd, J=15.3, 5.4 Hz, 1H), 5.54 (ddd,J=15.3, 8.1, 0.9 Hz, 1H), 4.42 (m, 1H), 4.14 (m, 1H), 4.06-1.10 (m,18H).

EXAMPLE 3(u)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.26 (Chloroform:Methanol=8: 1); NMR: δ 7.06-6.88 (m, 3H), 5.75(dd, J=15.3, 5.4 Hz, 1H), 5.51 (dd, J=15.3, 8.4 Hz, 1H), 4.39 (m, 1H),4.12 (m, 1H), 3.80-2.80 (br, 2H), 3.63 (m, 1H), 2.99 (m, 1H), 2.86-2.06(m, 14H), 1.98-1.62 (m, 3H).

EXAMPLE 3(v)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.22 (Chloroform:Methanol=8: 1); NMR: δ 7.24 (m, 1H), 7.13-7.04(m, 2H), 5.75 (dd, J=15.3, 5.7 Hz, 1H), 5.51 (ddd, J=15.3, 8.4, 0.9 Hz,1H), 4.40 (m, 1H), 4.13 (m, 1H), 4.10-3.10 (br, 2H:), 3.63 (m, 1H), 2.99(m, 1H), 2.88-2.14 (m, 11H), 2.00-1.56 (m, 3H).

EXAMPLE 3(w)(15β,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.48 (Chloroform:Methanol=9:1); NMR: δ 7.32-7.18 (m, 3H), 7.10(m, 1H), 5.75 (dd, J=15.0, 6.6 Hz, 1H), 5.41 (dd, J=15.0, 8.7 Hz, 1H),4.39 (m, 1H), 4.11 (m, 1H), 3.62 (m, 1H), 3.18-2.12 (m, 13H), 1.98-1.82(m, 2H), 1.60 (m, 1H).

EXAMPLE 3(x)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.62 (Chloroform:Methanol:Acetic Acid=18:2:1); NMR: δ 8.17 (s,1H), 7.14 (t, J=8 Hz, 1H), 7.0-6.9 (m, 3H), 5.68 (dd, J=15, 7Hz, 1H),5.35 (dd, J=15, 9 Hz, 1H), 4.31 (q, J=7 Hz, 1H), 4.25-4.1 (m, 1H),3.7-3.55 (m, 1H), 3.4-3.2 (m, 2H), 3.05-2.9 (m, 1H), 2.88 (dd, J=13,6Hz, 1H), 2.63 (dd, J=13, 7 Hz, 1H), 2.4-2.25 (m, 5H), 2.25-2.1 (m, 1H),1.75-1.6 (m, 1H).

EXAMPLE 3(y)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-4-(3-hydroxyisoxazol-5-yl)-1,2,3,17,18,19,20-heptanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.44 (Chloroform:Methanol=8: 1); NMR: δ 7.25-7.16 (m, 3H), 7.08(m, 1H), 5.87 (s, 1H), 5.72 (dd, J=15.3, 5.7 Hz, 1H), 5.48 (ddd, J=15.3,8.4, 1.2 Hz, 1H), 4.44 (m, 1H), 4.06 (m, 1H), 3.75-3.52 (m, 3H), 2.93(m, 1H), 2.88-2.48 (m, 6H), 2.42-2.30 (m, 2H), 2.22 (m, 1H), 1.67 (m,1H).

Hydrolysis of the ester (procedure of Example 2) was not done. Thehydroxyl group bound isoxazole ring was protected by methoxymethylgroup, and was removed protecting group at final step.

EXAMPLE 3(z)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-oxadiazol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.39 (Chloroform:Methanol=9:1); NMR: δ 7.38-7.15 (m, 3H),7.14-7.02 (m, 1H), 5.74 (dd, J=15.3, 6.0 Hz, 1H), 5.46 (ddd, J=15.3,8.7, 1.0 Hz, 1H), 4.41 (m, 1H), 4.02 (m, 1H), 3.57 (m, 1H), 3.00-2.19(m, 12H), 2.17-1.60 (m, 3H).

Hydrolysis of the ester (procedure of Example 2) was not done. The NHgroup bound 1,2,4-oxadiazole ring was protected by Boc group, and wasremoved protecting group at final step.

EXAMPLE 3(aa)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-thiadiazol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.30 (Chloroform:Methanol=9:1); NMR: δ 7.37-7.18 (m, 3H),7.12-7.04 (m, 1H), 5.74 (dd, J=15.0, 6.0 Hz, 1H), 5.47 (ddd, J=15.0,8.7, 1.2 Hz, 1H), 4.42 (m, 1H), 4.03 (m, 1H), 3.60 (m, 1H), 3.00-2.70(m, 4H), 2.69-2.38 (m, 7H), 2.28 (m, 1H), 2.15-1.70 (m, 3H).

Hydrolysis of the ester (procedure of Example 2) was not done. The NHgroup bound 1,2,4-oxadiazole ring was protected by Boc group, and wasremoved protecting group at final step.

EXAMPLE 3(bb)(15α,13E)-1-Methoxy-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.57 (Chloroform:Methanol=9:1); NMR: δ 7.32-7.18 (m, 3H), 7.10(m, 1H), 5.74 (dd, J=15.4, 5.8 Hz, 1H), 5.51 (ddd, J=15.4 8.5, 0.8 Hz,1H), 4.41 (m, 1H), 4.14 (m, 1H), 3.62 (m, 1H), 3.40 (m, 2H), 3.32 (s,3H), 2.94 (m, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.71-2.48 (m, 4H), 2.42-2.35(m, 2H), 2.24 (m, 1H), 1.77-1.63 (m, 5H).

Hydrolysis of the ester (procedure of Example 2) was not done.

EXAMPLE 3(cc)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.18 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.09 (s,1H), 7.18-7.12 (m, 2H), 7.06-6.95 (m, 2H), 5.79 (dd, J=15.3, 5.7 Hz,1H), 5.51 (dd, J=15.3, 9.0 Hz, 1H), 4.39 (m, 1H), 4.11 (m, 1H), 3.73 (m,1H), 3.40-2.19 (m, 10H), 1.74 (m, 1H).

EXAMPLE 3(dd)(15α,13E)-1-Methoxy-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-ene

TLC: Rf 0.59 (Chloroform:Methanol=9: 1); NMR: δ 7.19-7.15 (m, 2H),7.04-6.98 (m, 2H), 5.74 (dd, J=15.3, 5.7 Hz, 1H), 5.50 (dd, J=15.3, 8.4,1.2 Hz, 1H), 4.37 (m, 1H), 4.10 (m, 1H), 3.62 (m, 1H), 3.40-3.36 (m,2H), 3.30 (s, 3H), 2.96 (m, 1H), 2.88-2.75 (m, 2H), 2.69-2.49 (m, 4H),2.40-2.34 (m, 2H), 2.24 (m, 1H), 1.76-1.64 (m, 5H).

Hydrolysis of the ester (procedure of Example 2) was not done.

EXAMPLE 3 (ee)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxadiazol-3-yl-)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.50 (Chloroform:Methanol:Acetic Acid=9:1:0.2);NMR(CDCl₃+CD₃)D): δ 8.03 (s, 1H), 7.20-7.07 (m, 2H), 7.02-6.94 (m, 2H),5.72 (dd, J=15.3, 5.7 Hz, 1H), 5.44 (dd, J=15.3, 8.7 Hz, 1H), 4.35 (m,1H), 4.14 (m, 1H), 3.68 (m, 1H), 3.65-3.10 (m, 3H), 2.91-2.67 (m, 2H),2.46-2.11 (m, 3H), 1.72 (m, 1H).

Hydrolysis of the ester (procedure of Example 2) was not done. The NHgroup bound 1,2,4-oxadiazole ring was protected by Boc group, and wasremoved protecting group at final step.

EXAMPLE 3(ff)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoicacid

TLC: Rf 0.35 (Chloroform:Methanol=9:1); NMR: δ 7.32-7.20 (m, 3H), 7.10(m, 1H), 5.88 (dd, J=15.4, 5.2 Hz, 1H), 5.56 (ddd, J=15.4, 8.5, 1.4 Hz,1H), 4.50-4.29 (m, 2H), 4.43 (dd, J=8.5, 8.2 Hz, 1H), 3.89 (dd, J=8.5,8.2 Hz, 1H), 3.46 (m, 1H), 3.10 (m, 1H), 2.84-2.80 (m, 2H), 2.77-2.44(m, 6H), 1.98-1.87 (m, 2H).

EXAMPLE 3(gg)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoicacid

TLC: Rf 0.34 (Chloroform:Methanol=9:1); NMR: δ 7.20-7.13 (m, 2H),7.08-6.98 (m, 2H), 5.88 (dd, J=15.4, 5.2 Hz, 1H), 5.57 (ddd, J=15.4,8.5, 1.4 Hz, 1H), 4.47-4.28 (m, 2H), 4.42 (dd, J=8.5, 8.2 Hz, 1H), 3.91(dd, J=8.5, 8.2 Hz, 1H), 3.46 (m, 1H), 3.12 (m, 1H), 2.90-2.78 (m, 2H),2.75-2.43 (m, 6H), 1.97-1.86 (m, 2H).

EXAMPLE 3(hh)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoicacid

TLC: Rf 0.35 (Chloroform:Methanol=9:1); NMR: δ 7.22 (t, J=7.4 Hz, 1H),7.11-6.97 (m, 3H), 5.90 (dd, J=15.4, 5.2 Hz), 1H), 5.57 (ddd, J=15.4,8.8, 1.4 Hz, 1H), 4.51-4.28 (m, 3H), 3.91 (dd, J=8.2, 8.0 Hz, 1H), 3.45(m, 1H), 3.11 (m, 1H), 2.89-2.44 (m, 8H), 2.36 (s, 3H), 1.96-1.85 (m,2H).

EXAMPLE 3(ii)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylaminomethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid hydrochloride

TLC: Rf 0.11 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR(CD₃OD): δ7.50-7.30 (m, 4H), 5.76 (dd, J=15.0, 6.6 Hz, 1H), 5.45 (dd, J=15.0, 8.7Hz, 1H), 4.40 (m, 1H), 4.24-4.11 (m, 3H), 3.50 (m, 1H), 2.96-2.80 (m,3H), 2.71 (s, 3H), 2.63-2.43 (m, 3H), 2.42-2.20 (m, 4H), 1.93-1.62 (m,3H).

The amino group bound benzene ring was protected by Boc group, and wasremoved protecting group at final step.

EXAMPLE 3(jj)(15α,13E)-9-Oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.35 (Chloroform:Methanol=9:1); NMR: δ 7.08-6.93 (m, 3H), 5.75(dd, J=15.3, 5.4 Hz, 1H), 5.52 (ddd, J=15.3, 8.7, 1.2 Hz, 1H), 4.40 (m,1H), 4.12 (m, 1H), 3.62 (m, 1H), 3.00 (m, 1H), 2.87-2.18 (m, 11H),1.98-1.82 (m, 2H), 1.71 (m, 1H), 1.22 (t, J=7.5 Hz, 3H).

EXAMPLE 3(kk)(15α,13E)-9-Oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.34 (Chloroform:Methanol=9:1); NMR: δ 5.99 (d, J=2.7 Hz, 1H),5.88 (m, 1H), 5.75 (dd, J=15.3, 5.4 Hz, 1H), 5.55 (ddd, J=15.3, 8.7, 1.0Hz, 1H), 4.47 (m, 1H), 4.15 (m, 1H), 3.63 (m, 1H), 3.06 (m, 1H),2.92-2.78 (m, 2H), 2.75-2.18 (m, 12H), 2.00-1.81 (m, 2H), 1.72 (m, 1H).

EXAMPLE 3(ll)(15α,13E)-9-Oxo-15-hydroxy-16-(2-methyloxazol-5-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.35 (Chloroform:Methanol:Acetic Acid=18:2:1); NMR: δ 6.95 (s,1H), 5.80 (dd, J=16, 5 Hz, 1H), 5.66 (dd, J=16, 8 Hz, 1H), 4.6-4.5 (m,1H), 4.25-4.1 (m, 1H), 3.7-3.55 (m, 1H), 3.2-3.05 (m, 1H), 3.0-2.8 (m,2H), 2.75-2.5 (m, 7H), 2.5-2.35 (m, 4H), 2.35-2.2 (m, 1H), 2.0-1.85 (m,2H), 1.85-1.7 (m, 1H).

EXAMPLE 3(mm)(15α,13E)-9-Oxo-15-hydroxy-16-(benzofuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.43 (Chloroform:Methanol=19:1); NMR: δ 7.55-7.5 (m, 1H), 7.41(d, J=7 Hz, 1H4), 7.25-7.15 (m, 2H), 6.52 (s, 1H), 5.80 (dd, J=15, 6 Hz,1H), 5.57 (dd, J=15, 8 Hz, 1H), 4.63 (q, J=6 Hz, 1H4), 4.15-4.05 (m,1H), 3.58 (pent, J=7 Hz, 1H), 3.04 (d, J=6 Hz, 2H), 3.0-2.9 (m, 1H),2.65-2.3 (m, 8H), 2.3-2.1 (m, 1H), 1.95-1.8 (m, 2H), 1.75-1.6 (m, 1H).

EXAMPLE 3(nn)(15α,13E)-9-Oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.29 (Chloroform:Methanol=9:1); NMR: δ 6.00 (d, J=3.0 Hz, 1H),5.88 (d, J=3.0 Hz, 1H), 5.75 (dd, J=15.3, 5.4 Hz, 1H), 5.55 (ddd,J=15.3, 8.4, 1.0 Hz, 1H), 4.48 (m, 1H), 4.15 (m, 1H), 3.64 (m, 1H), 3.03(m, 1H), 2.93-2.78 (m, 2H), 2.71-2.18 (m, 12H), 1.99-1.82 (m, 2H), 1.72(m, 1H), 1.21 (t, J=7.2 Hz, 3H).

EXAMPLE 3(oo)(15α,13E)-9-Oxo-15-hydroxy-16-(4,5-dimethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.31 (Chloroform:Methanol=9:1); NMR: δ 5.89 (s, 1H), 5.75 (dd,J=15.3, 5.1 Hz, 1H), 5.55 (dd, J=15.3, 8.7 Hz, 1H), 4.44 (m, 1H), 4.15(m, 1H), 3.63 (m, 1H), 3.07 (m, 1H), 2.86-2.09 (m, 15H), 1.99-1.63 (m,6H).

EXAMPLE 3(pp)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.41 (Chloroform:Methanol=9:1); NMR: δ 7.24 (d, J=1.8 Hz, 1H),6.19 (d, J=1.8 Hz, 1H), 5.75 (dd, J=16, 6 Hz, 1H), 5.53 (dd, J=16, 9 Hz,1H), 4.53-4.44 (m, 1H), 4.18-4.08 (m, 1H), 3.70-3.59 (m, 1H), 3.10-2.97(m, 1H), 2.83 (d, J=6 Hz, 2H), 2.72-2.32 (m, 8H), 2.30-2.18 (m, 1H),2.0-1.8 (m, 5H), 1.81-1.64 (m, 1H).

EXAMPLE 3(gg)(15α,13E)-9-Oxo-15-hydroxy-16-(3-nitrophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.59 (Chloroform:Methanol=9:1); NMR: δ 8.01 (m, 1H), 7.60-7.42(m, 3H), 5.78 (dd, J=15.0, 5.4 Hz, 1H), 5.55 (dd, J=15.0, 8.4 Hz, 1H),4.50 (m, 1H), 4.16 (m, 1H), 3.60 (m, 1H), 3.10-2.18 (m, 13H), 1.98-1.81(m, 2H), 1.78-1.59 (m, 1H).

EXAMPLE 3(rr) (15α,13E)-9-Oxo-15-hydroxy-16-(3-methylisoxazol-5-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf 0.42 (Chloroform:Methanol=9:1); NMR: δ 5.96 (s, 1H), 5.79 (dd,J=15.3, 5.1 Hz, 1H), 5.60 (dd, J=15.3, 8.1 Hz, 1H), 4.59 (m, 1H), 4.17(m, 1H), 4.00-3.20 (m, 2H), 3.10-2.99 (m, 3H), 2.75-2.20 (m, 12H),1.98-1.80 (m, 2H), 1.71 (m, 1H).

EXAMPLE 4(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol

To a solution of the compound prepared in Example 1 (220 mg) intetrahydrofuran (2 mL), lithium borohydride (23 mg) was added at roomtemperature, and the mixture was stirred for 2.5 hours at roomtemperature then 3 hours at 50° C. After cooling, the mixture was addedby ethanol and water, and extracted by ethyl acetate. The organic layerwas washed with brine, dried over an anhydrous sodium sulfate,concentrated under reduced pressure and was purified by columnchromatography on silica gel (from ethyl acetate:hexane=from 50:1 to10:1) to give the title compound (171 mg) having the following physicaldata.

TLC: Rf 0.16 (Ethyl Acetate:Methanol=85:15); NMR: δ 7.38-7.11 (m, 4H),5.73 (dd, J=15.3, 6.0 Hz, 1H), 5.50 (ddd, J=15.3, 8.0, 1.2 Hz, 1H),4.50-4.37 (m, 3H), 4.08-3.99 (m, 1H), 3.62 (t, J=6.6 Hz, 2H), 3.53-3.37(m, 4H), 2.92-2.70 (m, 3H), 2.46-2.12 (m, 3H), 1.94 (bs, 1H), 1.78-1.20(m, 12H).

EXAMPLE 4(a) to EXAMPLE 4(w)

By the same procedure as describe in Example 4 using correspondingcarboxylic acid ester derivatives instead of the compound prepared inExample 1, the compound of the present invention having the followingphysical data were obtained.

Example 4(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.18 (Ethyl Acetate:Methanol=50:1); NMR: δ 7.35-7.10 (m, 4H),5.77 (dd, J=15, 6 Hz, 1H), 5.52 (dd, J=15, 9 Hz, 1H), 4.43 (s, 2H),4.45-4.35 (m, 1H), 4.15-4.05 (m, 1H), 3.70-3.55 (m, 3H), 3.42 (s, 3H),3.05-2.95 (m, 1H), 2.9-2.75 (m, 2H), 2.7-2.45 (m, 4H), 2.4-2.3 (m, 2H),2.3-2.15 (m, 1H), 2.1-1.9 (br, 2H), 1.8-1.5 (m, 5H).

EXAMPLE 4(b)(15α,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-en1-ol

TLC: Rf 0.18 (Ethyl Acetate); NMR: δ 7.15-7.00 (m, 2H), 6.93 (m, 1H),5.72 (dd, J=15.4, 5.8 Hz, 1H), 5.50 (dd, J=15.4, 9.3 Hz, 1H), 4.38 (m,1H), 4.03 (m, 1H), 3.62 (t, J=6.3 Hz, 2H), 3.48 (m, 1H), 2.80 (d, J=6.6Hz, 2H), 2.74 (m, 1H), 2.46-2.26 (m, 2H), 2.22 (m, 1H), 1.76-1.20 (m,1H).

EXAMPLE 4(c)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol

TLC: Rf 0.39 (Chloroform:Methanol=9:1); NMR: δ 7.24-7.18 (m, 3H), 7.08(m, 1H), 5.71 (dd, J=15.4, 6.0 Hz, 1H), 5.48 (ddd, J=15.4, 8.2, 0.8 Hz,1H), 4.42 (m, 1H), 4.04 (m, 1H), 3.63 (t, J=6.6 Hz, 2H), 3.47 (m, 1H),2.82 (d, J=6.6 Hz, 2H), 2.72 (m, 1H), 2.44-2.26 (m, 2H), 2.21 (m, 1H),1.77-1.20 (m, 11H).

EXAMPLE 4(d)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.17 (Ethyl Acetate); NMR: δ 7.29-7.19 (m, 3H), 7.08 (m, 1H),5.74 (dd, J=15.4, 5.8Hz, 1H), 5.49 (dd, J=15.4, 8.5 Hz, 1H), 4.40 (m,1H), 4.10 (m, 1H), 3.70-3.67 (m, 2H), 3.65 (m, 1H), 2.95 (m, 1H), 2.84(d, J=6.6 Hz, 2H), 2.68-2.47 (m, 4H), 2.40-2.34 (m, 2H), 2.23 (m, 1H),2.09 (br. s, 1H), 1.75-1.58 (m, 5H).

EXAMPLE 4(e)(15α,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1ol

TLC: Rf 0.18 (Ethyl Acetate); NMR: δ 7.37-7.16 (m, 5H), 5.76 (dd,J=15.4, 5.8Hz, 1H), 5.49 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.42 (m, 1H),4.09 (m, 1H), 3.71-3.56 (m, 3H), 2.96 (m, 1H), 2.84 (d, J=6.6 Hz, 2H),2.67-2.43 (m, 4H), 2.41-2.35 (m, 2H), 2.23 (m, 1H), 1.79-1.60 (m, 5H).

EXAMPLE 4(f)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.32 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.21 (t, J=7.4Hz, 1H), 7.19-6.97 (m, 3H), 5.76 (dd, J=15.4, 5.8 Hz, 1H), 5.50 (ddd,J=15.4, 8.5, 1.1 Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.68-3.58 (m, 3H),2.95 (m, 1H), 2.84-2.78 (m, 2H), 2.67-2.48 (m, 4H), 2.41-2.35 (m, 2H),2.36 (s, 3H), 2.26 (m, 1H), 1.78-1.62 (m, 5H).

EXAMPLE 4(g)(15α,13E)-9-Oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.35 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.29 (m, 1H),7.01-6.89 (m, 3H), 5.75 (dd, J=15.4, 5.8Hz, 1H), 5.50 (ddd, J=15.4, 8.5,1.1 Hz, 1H), 4.41 (m, 1H), 4.12 (m, 1H), 3.70-3.57 (m, 3H), 2.94 (m,1H), 2.84 (d, J=6.6 Hz, 2H), 2.66-2.54 (m, 4H), 2.41-2.35 (m, 2H), 2.24(m, 1H), 1.78-1.60 (m, 5H).

EXAMPLE 4(h)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.35 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.20-7.13 (m,2H), 7.05-6.96 (m, 2H), 5.74 (dd, J=15.4, 5.5 Hz, 1H), 5.50 (ddd,J=15.4, 8.5, 1.4 Hz, 1H), 4.38 (m, 1H), 4.10 (m, 1H), 3.71-3.57 (m, 3H),2.95 (m, 1H), 2.82 (d, J=6.9 Hz, 2H), 2.66-2.48 (m, 4H), 2.40-2.33 (m,2H), 2.24 (m, 1H), 1.78-1.60 (m, 5H).

EXAMPLE 4(i)(15α,13E)-9-Oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.20 (Ethyl Acetate); NMR: δ 7.21 (d, J=7.8 Hz, 1H), 7.06 (d,J=7.8 Hz, 1H), 7.04-7.00 (m, 2H), 5.76 (dd, J=15.0, 6.0 Hz, 1H), 5.51(ddd, J=15.0, 8.0, 1.2 Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 3.72-3.59(m, 3H), 2.98 (m, 1H), 2.90-2.78 (m, 2H), 2.73-2.43 (m, 8H), 2.41-2.10(m, 3H), 1.90 (bs, 1H), 1.80-1.75 (m, 6H), 0.94 (t, J=7.5 Hz, 3H).

EXAMPLE 4(j)(15α,13E)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.20 (Ethyl Acetate); NMR: δ 7.60-7.30 (m, 4H), 5.76 (dd,J=15.0, 5.7 Hz, 1H), 5.52 (ddd, J=15.0, 8.0, 10 Hz, 1H), 4.43 (m,1H),4.11 (m, 1H), 3.73-3.69 (m, 3H), 3.06-2.83 (m, 3H), 2.72-2.50 (m,4H), 2.42-2.00 (m, 5H), 1.80-1.53 (m, 5H).

EXAMPLE 4(k)(15α,13E)-9-Oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.43 (Chloroform:Methanol=9:1); NMR: δ 7.24 (m, 1H), 7.13-6.98(m, 3H), 5.78 (dd, J=15.4, 6.0 Hz, 1H), 5.52 (ddd, J=15.4, 8.5, 1.1 Hz,1H), 4.41 (m, 1H), 4.12 (m, 1H), 3.68-3.57 (m, 3H), 3.00 (m, 1H),2.90-2.75 (m, 2H), 2.67-2.52 (m, 6H), 2.42-2.35 (m, 2H), 2.25 (m, 1H),1.77-1.60 (m, 5H), 1.23 (t, J=7.7 Hz, 3H).

EXAMPLE 4(l)(15α,13E)-9-Oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.18 (Ethyl Acetate); NMR: δ 7.15-7.00 (m, 2H), 6.93 (m, 1H),5.74 (dd, J=15.4, 5.5 Hz, 1H), 5.52 (dd, J=15.4, 8.5 Hz, 1H), 4.38 (m,1H), 4.12 (m, 1H), 3.71-3.57 (m, 3H), 2.98 (m, 1H), 2.80 (d, J=6.9 Hz,2H), 2.68-2.48 (m, 4H), 2.42-2.36 (m, 2H), 2.25 (m, 1H), 1.77-1.60 (m,5H).

EXAMPLE 4(m)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.47 (Chloroform:Methanol=8:1); NMR: δ 7.52-7.34 (m, 2H), 7.15(dd, J=9.6, 9.6 Hz, 1H), 5.76 (dd, J=15.3, 5.4 Hz, 1H), 5.53 (ddd,J=15.3, 8.7, 0.9 Hz, 1H), 4.42 (m, 1H), 4.12 (m, 1H), 3.74-3.54 (m, 3H),3.26-1.40 (m, 17H).

EXAMPLE 4(n)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.33 (Chloroform:Methanol=8:1); NMR: δ 7.06-6.90 (m, 3H), 5.75(dd, J=15.3, 5.4 Hz, 1H), 5.51 (ddd, J=15.3, 8.4, 0.9 Hz, 1H), 4.37 (m,1H), 4.10 (m, 1H), 3.74-3.56 (m, 3H), 2.99 (m, 1H), 2.86-2.16 (m, 12H),2.00-1.44 (m, 7H).

EXAMPLE 4(o)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.35 (Chloroform:Methanol=8:1); NMR: δ 7.26 (m, 1H), 7.14-7.04(m, 2H), 5.74 (dd, J=15.3, 5.4 Hz, 1H), 5.51 (ddd, J=15.3, 8.7, 0.9 Hz,1H), 4.39 (m, 1H), 4.11 (m, 1H), 3.78-3.56 (m, 3H), 2.99 (m, 1H),2.84-1.86 (m, 10H), 1.82-1.54 (m, 6H).

EXAMPLE 4(p)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-ol

TLC: Rf 0.22 (Ethyl Acetate); NMR: δ 7.19 (t, J=7.4 Hz, 1H), 7.08-6.94(m, 3H), 6.79 (d, J=3.3 Hz, 1H), 6.64 (d, J=3.3 Hz, 1H), 5.69 (dd,J=15.4, 6.0 Hz, 1H), 5.43 (ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.72 (s, 2H),4.37 (m, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 2.85-2.74 (m, 5H), 2.44-2.33(m, 2H), 2.36 (s, 3H), 2.20 (m, 1H), 1.87-1.64 (m, 3H).

EXAMPLE 4(q)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-hydroxymethylthiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.20 (Ethyl Acetate); NMR: δ 7.48 (s, 1H), 7.20 (t, J=8 Hz, 1H),7.1-6.95 (m, 3H), 5.68 (dd, J=15, 6Hz, 1H), 5.47 (dd, J=15, 9 Hz, 1H),4.78 (s, 2H), 4.34 (q, J=6 Hz, 1H), 4.13 (q, J=7Hz, 1H), 3.7-3.6 (m,1H), 3.4-3.15 (m, 3H), 2.77 (d, J=6Hz, 2H), 2.4-2.1 (m, 6H), 1.8-1.6 (m,1H).

EXAMPLE 4(r)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-en-1-ol

TLC: Rf 0.36 (Chloroform:Methanol=9:1); NMR: δ 7.32-7.20 (m, 3H), 7.10(m, 1H), 5.86 (dd, J=15.4, 5.5 Hz, 1H), 5.56 (ddd, J=15.4, 8.8, 1.4 Hz,1H), 4.48-4.29 (m, 2H), 4.43 (dd, J=8.2, 8.2 Hz, 1H), 3.91 (dd, J=8.2,8.2 Hz, 1H), 3.70-3.63 (m, 2H), 3.45 (m, 1H), 3.09 (m, 1H), 2.82 (d,J=6.0 Hz, 2H), 2.75-2.56 (m, 4H), 1.78-1.54 (m, 4H).

EXAMPLE 4(s)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-en-1-ol

TLC: Rf 0.37 (Chloroform:Methanol=9:1); NMR: δ 7.20-7.13 (m, 2H),7.06-6.98 (m, 2H), 5.87 (dd, J=15.4, 5.5 Hz, 1H), 5.57 (ddd, J=15.4,8.5, 1.4 Hz, 1H), 4.44-4.28 (m, 2H), 4.43 (dd, J=8.5, 8.2 Hz, 1H), 3.91(dd, J=8.5, 8.2 Hz, 1H), 3.69-3.64 (m, 2H), 3.46 (m, 1H), 3.11 (m, 1H),2.90-2.76 (m, 2H), 2.74-2.55 (m, 4H), 1.78-1.62 (m, 4H).

EXAMPLE 4(t)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienylene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-en-1-ol

TLC: Rf 0.46 (Ethyl Acetate:Methanol=19:1); NMR: δ 7.25-7.1 (m, 2H),7.05-6.95 (m, 2H), 6.66 (d, J=3Hz, 1H), 6.62 (d, J=3 Hz, 1H), 5.73 (dd,J=16, 6 Hz, 1H), 5.47 (dd, J=16, 9 Hz, 1H), 4.85 (d, J=15 Hz, 1H),4.45-4.35 (m, 1H), 4.05-3.95 (m, 1H), 3.88 (d, J=15 Hz, 1H), 3.70 (t,J=6 Hz, 2H), 2.95-2.8 (m, 4H), 2.5-2.3 (m, 2H), 2.25-2.1 (m, 1H),2.0-1.85 (m, 2H), 1.8-1.6 (m, 1H).

EXAMPLE 4(u)(15α,13E)-9-Oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.28 (Ethyl Acetate:Methanol=9:1); NMR: δ 7.06-6.91 (m, 3H),5.75 (dd, J=15.6, 5.7 Hz, 1H), 5.52 (ddd, J=15.6, 9.0, 1.5 Hz, 1H), 4.39(m, 1H), 4.10 (m, 1H), 3.72-3.59 (m, 3H), 3.00 (m, 1H), 2.84-2.43 (m,8H), 2.41-2.19 (m, 3H), 1.90 (bs, 2H), 1.80-1.60 (m, 5H), 1.22 (t, J=7.5Hz, 3H).

EXAMPLE 4(v)(15α,13E)-9-Oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol

TLC: Rf 0.35 (Ethyl Acetate:Methanol=19:1); NMR: δ 5.99 (d, J=3.0 Hz,1H), 5.88 (m, 1H), 5.76 (dd, J=15.3, 5.7 Hz, 1H), 5.55 (ddd, J=15.3,8.4, 1.0 Hz, 1H), 4.42 (m, 1H), 4.11 (m, 1H), 3.74-3.60 (m, 3H), 3.06(m, 1H), 2.94-2.77 (m, 2H), 2.71-2.50 (m, 4H), 2.43-2.09 (m, 7H),1.92-1.56 (m, 6H).

EXAMPLE 4(w)(15α,13E)-9-Oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-13-en-1-ol

TLC: Rf 0.16 (Ethyl Acetate:Methanol=19:1); NMR: δ 6.01 (d, J=3.0 Hz,1H), 5.89 (d, J=3.0 Hz, 1H), 5.75 (dd, J=15.3, 5.4 Hz, 1H), 5.55 (dd,J=15.3, 8.7 Hz, 1H), 4.45 (m, 1H), 4.10 (m, 1H), 3.71-3.59 (m, 3H), 3.03(m, 1H), 2.92-2.78 (m, 2H), 2.72-2.45 (m, 6H), 2.42-2.10 (m, 4H),2.00-1.59 (m, 6H), 1.21 (t, J=7.8 Hz, 3H).

EXAMPLE 5(15α)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprostanoicacid ethyl ester

Under atmosphere of argon, Palladium on carbon (44 mg) was added to thesolution of the compound prepared in Example 1 (440 mg) in ethanol (10mL), and argon was displaced by hydrogen. After the mixture was stirredfor 4 hours, the catalyst was removed by filtration. The filtrate wasconcentrated under reduced pressure and was purified by columnchromatography on silica gel (ethyl acetate:methanol=from 50:1 to 20:1)to give the title compound (384 mg) having the following physical data.

TLC: Rf 0.16 (Ethyl Acetate:Methanol=85:15).

EXAMPLE 6(15α)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprostanoicacid

By the same procedure as describe in Example 2 using the compoundprepared in Example 5 (227 mg) instead of the compound prepared inExample 1, the compound (173 mg) of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.45 (Chloroform:Methanol=9:1); NMR: δ 7.38-7.11(m, 4H), 4.45(s, 2H), 3.91-3.80 (m, 1H), 3.67-3.53 (m, 2H), 3.42 (s, 3H), 3.00-2.64(m, 3H), 2.50-2.03 (m, 5H), 1.94-1.89 (m, 1H), 1.86-1.20 (m, 13H).

EXAMPLE 6(a) to EXAMPLE 6(c)

By the same procedure as describe in Examples 5 and 6 usingcorresponding carboxylic acid ester derivatives instead of the compoundprepared in Example 1, the compound of the present invention having thefollowing physical data were obtained.

EXAMPLE 6(a)(15α)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprostanoicacid

TLC: Rf 0.37 (Chloroform:Methanol=10:1); NMR: δ 7.22 (t, J=6.9 Hz, 1H),7.08-6.99 (m, 3H), 3.86 (m, 1H), 3.63-3.54 (m, 2H), 2.92 (m, 1H), 2.80(dd, J=13.5, 4.8 Hz, 1H), 2.67 (dd, J=13.5, 8.4 Hz, 1H), 2.34 (s, 3H),2.40-1.20 (m, 18H).

EXAMPLE 6(b)(15α)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprostanoicacid

TLC: Rf 0.32 (Chloroform:Methanol=10:1); NMR: δ 7.21 (t, J=7.8 Hz, 1H),7.08-6.98 (m, 3H), 3.90 (m, 1H), 3.78-3.62 (m, 2H), 3.40 (br s, 1H),3.17 (m, 1H), 2.80-2.30 (m, 10H), 2.34 (s, 3H), 2.14 (m, 1H), 2.00-1.40(m, 7H).

EXAMPLE 6(c)(15α)-9-Oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprostanoicacid

TLC: Rf 0.6 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.57-7.39 (m,4H), 3.95 (m, 1H), 3.78-3.63 (m, 2H), 3.19 (m, 1H), 2.92-2.67 (m, 4H),2.65-2.34 (m, 6H), 2.16 (m, 1H), 2.00-1.47 (m, 7H).

REFERENCE EXAMPLE 12(15α,13E)-9-Oxo-15-(t-butyldimethylsilyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid ethyl ester

A solution of the compound prepared in Example 1 (1.26 g) indimethylformamide (3 mL) was cooled, and was added by the solution ofimidazole (275 mg) and t-butyldimethylsilyl chloride (446 mg) indimethylformamide (2 mL). After the mixture was stirred for 1 hour atroom temperature, water was added hereto, and was extracted by ethylacetate. The extraction was washed with water and brine successively,dried over an anhydrous sodium sulfate, concentrated under reducedpressure to give the title compound (3.39 g) having the followingphysical data.

TLC: Rf 0.62 (Ethyl Acetate).

REFERENCE EXAMPLE 13(15α,13E)-9-Oxo-15-(t-butyldimethylsilyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

To a solution of the compound prepared in Reference Example 12 (420 mg)in mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), 2Naqueous sodium hydroxide (1.2 mL) was added, and the mixture was stirredfor 2 hours. Hydrochloric acid was added to the mixture to acidify, thenwas extracted by ethyl acetate. The extract was washed with brine, driedover an anhydrous sodium sulfate, concentrated under reduced pressure togive the title compound (398 mg) having the following physical data.

TLC: Rf 0.48 (Chloroform:Methanol=8:1).

REFERENCE EXAMPLE 14(15α,13E)-9-Oxo-15-(t-butyldimethylsilyloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid N-mesylamide

To a solution of the compound prepared in Reference Example 13 (90 mg)in methylene chloride (1 mL), methansulfonamide (41 mg),dimethylaminopyridine (32 mg) andI-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydyochloride (67 mg)was added, and the mixture was stirred overnight at room temperature.Diluted hydrochloric acid was added to the mixture, then was extractedby ethyl acetate. The extract was washed with brine, dried over ananhydrous sodium sulfate, concentrated under reduced pressure to givethe title compound (100 mg) having the following physical data.

TLC: Rf 0.23 (Hexane:Ethyl Acetate=1:3).

EXAMPLE 7(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid N-mesylamide

To a solution of the compound prepared in Example 14 (100 mg) intetrahydrofuran (1 mL), tetrabutylammonium fluoride (0.35 mL; 1.0Mtetrahydrofuran solution) was added, and the mixture was stirred for 3hours at room temperature. The mixture was poured into cold aqueousammonium chloride solution, and extracted by ethyl acetate. The extractwas washed with brine, dried, concentrated under reduced pressure andwas purified by column chromatography on silica gel (from hexane:ethylacetate=1:3 to chloroform:methanol=10:1) to give the title compound (35mg) having the following physical data.

TLC: Rf 0.38 (Chloroform:Methanol=8:1); NMR: δ 9.97 (brs, 1H), 7.38-7.08(m, 4H), 5.75 (dd, J=15.3, 5.4 Hz, 1H), 5.50 (dd, J=15.3, 8.1 Hz, 1H),4.44 (s, 2H), 4.43 (m, 1H), 4.04 (m, 1H), 3.41 (s, 3H), 3.40 (m, 1H),3.26 (s, 3H), 3.06-2.72 (m, 3H), 2.52-2.10 (m, 5H), 1.86-1.12 (m, 10H).

EXAMPLE 7(a) to EXAMPLE 7(d)

By the same procedure as describe in Reference Example 14 and Example 7using the compound prepared in Reference Example 13 or correspondingcarboxylic acid derivatives and corresponding sulfonamide derivativesinstead of methanesulfonamide, the compound of the present inventionhaving the following physical data were obtained.

EXAMPLE 7(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid N-phenylsulfonylamide

TLC: Rf 0.42 (Chloroform:Methanol=8:1); NMR: δ 9.84 (brs, 1H), 8.05 (d,J=7.2 Hz, 1H), 7.68-7.46 (m, 3H), 7.38-7.08 (m, 5H), 5.75 (dd, J=15.3,5.4 Hz, 1H), 5.50 (dd, J=15.3, 8.7 Hz, 1H), 4.45 (s, 2H), 4.45 (m, 1H),4.03 (m, 1H), 3.41 (s, 3H), 3.40 (m, 1H), 3.06-2.68 (m, 3H), 2.54-2.12(m, 5H), 1.90-1.06 (m, 10H).

EXAMPLE 7(b)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid N-benzylsulfonylamide

TLC: Rf 0.44 (Chloroform:Methanol=8:1); NMR: δ 9.46 (brs, 1H), 7.46-7.04(m, 9H), 5.71 (dd, J=15.3, 5.7 Hz, 1H), 5.46 (dd, J=15.3, 8.7 Hz, 1H),4.63 (s, 2H), 4.42 (s, 2H), 4.40 (m, 1H), 3.98 (m, 1H), 3.37 (s, 3H),3.30 (m, 1H), 3.00-2.62 (m, 3H), 2.40-2.06 (m, 5H), 1.82-1.08 (m, 10H).

EXAMPLE 7(c)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoicacid N-benzylsulfonylamide

TLC: Rf 0.12 (Chloroform:Methanol=9:1); NMR: δ 9.15 (br. s, 1H), 7.52(d, J=3.9 Hz, 1H), 7.39-7.30 (m, 5H), 7.18-7.11 (m, 2H), 7.03-6.96 (m,2H), 6.79 (d, J=3.9 Hz, 1H), 5.71 (dd, J=15.4, 5.8 Hz, 1H), 5.43 (ddd,J=15.4, 8.8, 1.1 Hz, 1H), 4.76 (s, 2H), 4.38 (m, 1H), 4.00 (m, 1H), 3.41(m, 1H), 2,86-2.74 (m, 5H), 2.38-2.07 (m, 3H), 1.84-1.60 (m, 3H).

EXAMPLE 7(d)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-benzylsulfonylcarbamoylthiazol-2-yl-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf 0.46 (Chloroform:Methanol:Acetic Acid=9:1:0.2); NMR: δ 8.20 (s,1H), 7.34 (s, 5H), 7.18-7.07 (m, 2H), 7.02-6.95 (m, 2H), 5.71 (dd,J=15.3, 5.1 Hz, 1H), 5.47 (dd, J=15.3, 9.0 Hz, 1H), 4.73 (s, 2H), 4.37(m, 1H), 4.03 (m, 1H), 3.63 (m, 1H), 3.39 (m, 1H), 3.28-3.10 (m, 2H),2.82-2.71 (m, 2H), 2.25-2.03 (m, 3H), 1.75-1.55 (m, 1H).

REFERENCE EXAMPLE 15(15α,13E)-9-Thioxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid butyl ester

To a solution of(15α,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid butyl ester (170 mg; this compound were obtained by the sameprocedure as describe in Reference Example 12 using(15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid butyl ester instead of the compound prepared in Example 1) intoluene (2 mL),2,4-bis(4-methoxyphenyl),1,3-dithia-2,4-diphosphetan-2,4-disulfide(Lawesson reagent) (74 mg) was added and the mixture was stirred for 1hour at 50° C. After cooling, the reaction mixture was purified bycolumn chromatography on silica gel (hexane:ethyl acetate=5:1) to givethe title compound (175 mg) having the following physical data.

TLC: Rf 0.53 (Hexane:Ethyl Acetate=4:1).

EXAMPLE 8(15α,13E)-9-Thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid butyl ester

To a solution of the compound prepared in Reference Example 15 (160 mg)in tetrahydrofuran (1.4 mL), tetrabutylammonium fluoride (1.4 mL; 1.0Mtetrahydrofuran solution) was added, and the mixture was stirred for 3hours at room temperature. The mixture was poured into saturated aqueousammonium chloride solution, and extracted by ethyl acetate. The extractwas washed with water and brine successively, dried over anhydroussodium sulfate, concentrated under reduced pressure and was purified bycolumn chromatography on silica gel (from hexane:ethyl acetate=2:1 toethyl acetate only) to give the title compound (110 mg) having thefollowing physical data.

TLC: Rf 0.38 (Hexane:Ethyl Acetate=1:1).

EXAMPLE 9(15α,13E)-9-Thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

By the same procedure as describe in Example 2 using the compoundprepared in Example 8 instead of the compound prepared in Example 1, thecompound of the present invention having the following physical datawere obtained.

TLC: Rf 0.40 (Chloroform:Methanol=8:1); NMR: δ 7.22 (dd, J=7.5, 7.5 Hz,1H), 7.11-6.95 (m, 3H), 5.82 (dd, J=15.3, 5.1 Hz, 1H), 5.55 (ddd,J=15.3, 8.7, 1.2 Hz, 1H), 4.52-4.38 (m, 2H), 4.13 (m, 1H), 3.37 (m, 1H),3.10-2.39 (m, 12H), 2.35 (s, 3H), 2.27 (m, 1H), 2.00-1.70 (m, 3H).

EXAMPLE 9(a)(15α,13E)-9-Thioxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoicacid

By the same procedure as describe in Reference Example 15, Examples 8and 9 using the compound prepared in Reference Example 12 instead of(15α,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid butyl ester, the compound of the present invention having thefollowing physical data were obtained.

TLC: Rf 0.31 (Methanol: Chloroform=1:10); NMR: δ 7.40-7.10 (m, 4H), 5.82(dd, J=15.4, 5.0 Hz, 1H), 5.59 (dd, J=15.4, 8.4 Hz, 1H), 4.50-4.25 (m,2H), 4.47 (s, 2H), 4.02-3.85 (m, 1H), 3.43 (s, 3H), 3.38-3.10 (m, 1H),3.10-2.75 (m, 4H), 2.40-2.15 (m, 2H), 2.33 (t, J=7.2 Hz, 2H), 1.90-1.20(m, 10H).

REFERENCE EXAMPLE 16(15α,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ylt-butoxycarbonylglycylglycinate

To a solution of(15α,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol(170 mg; this compound was prepared by protecting of hydroxy group atC15 position of the methyl ester of the compound prepared in Example3(j) by t-butyldimethylsilyl group (TBS group) followed by the sameprocedure as describe in Example 4) in mixed solvent of methlenechloride (2 mL) and dimethylformammide (1 mL),t-Butoxycarbonylglycylglycin (96 mg), methyl 3-methyl-2-fluoropyridiniumtosylate (257 mg) and diisopropylamine (0.18 mL) were added, and themixture was stirred overnight at room temperature. The reaction mixturewas poured into cold water, and was extracted by ethyl acetate. Theextract was washed with water and brine successively, dried overanhydrous sodium sulfate, concentrated under reduced pressure and waspurified by column chromatography on silica gel (from hexane:ethylacetate=1:2 to ethyl acetate only) to give the title compound (170 mg)having the following physical data.

TLC: Rf 0.53 (Chloroform:Methanol=8:1).

EXAMPLE 10(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ylt-butoxycarbonylglycylglycinate

To a solution of the compound prepared in Example 16 (170 mg) in dioxane(0.14 mL), 1N hydrochloric acid (0.14 mL) was added, and the mixture wasstirred overnight at room temperature. The mixture was poured intosaturated aqueous sodium chloride solution, and extracted by ethylacetate. The extract was dried over anhydrous sodium sulfate,concentrated under reduced pressure and was purified by columnchromatography on silica gel (from hexane:ethyl acetate=1:2 to ethylacetate only, then chloroform:methanol=30:1) to give the title compound(100 mg) having the following physical data.

TLC: Rf 0.33 (Chloroform:Methanol=8:1).

EXAMPLE 11(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ylglycylglycinate monohydrochloride

To a solution of the compound prepared in Example 10 (65 mg) in benzene(0.55 mL), 4N hydrogenchloride-ethyl acetate (0.14 mL) was added, andthe mixture was stirred for 2 hours at room temperature. The mixture wasazeotropied with toluene to give the title compound (54 mg) having thefollowing physical data.

TLC: Rf 0.41 (Chloroform:Methanol=4:1); NMR(CD₃OD): δ 7.15 (dd, J=7.5,7.5 Hz, 1H), 7.08-6.94 (m, 3H), 5.70 (dd, J=15.3, 6.6 Hz, 1H), 5.37 (dd,J=15.3, 8.7 Hz, 1H), 4.33 (m, 1H), 4.24-4.07 (m, 3H), 4.06-3.94 (m, 2H),3.73 (s, 2H), 3.60-3.40 (m, 2H), 2.95-2.12 (m, 14H), 1.82-1.54 (m, 5H).

EXAMPLE 11(a) to EXAMPLE 11(c)

By the same procedure as describe in Reference Example 16, Examples 10and 11 using corresponding amino acid derivatives instead oft-butoxycarbonylglycylglycine, the compound of the present inventionhaving the following physical data were obtained.

EXAMPLE 11(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ylglycinate methanesulfonic acid salt

TLC: Rf 0.27 (Chloroform:Methanol=8:1); NMR(CD₃OD): δ 7.15 (dd, J=7.5,7.5 Hz, 1H), 7.06-6.94 (m, 3H), 5.70 (dd, J=15.3, 6.6 Hz, 1H), 5.37(ddd, J=15.3, 8.7, 0.9 Hz, 1H), 4.33 (m, 1H), 4.27 (t, J=6.3 Hz, 2H),4.13 (m, 1H), 3.83 (s, 2H), 3.50 (m, 1H), 2.96-2.10 (m, 15H), 1.88-1.54(m, 5H).

EXAMPLE 11(b)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-l17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yltryptophanate bis-trifluoroacetic acid salt

TLC: Rf 0.40 (Chloroform:Methanol=8:1); NMR(CD₃OD): δ 7.53 (d, J=8.1 Hz,1H), 7.39 (d, J=8.1 Hz, 1H), 7.24-6.92 (m, 7H), 5.67 (dd, J=15.6, 6.6Hz, 1H), 5.34 (dd, J=15.6, 9.0 Hz, 1H), 4.30 (t, J=6.9 Hz, 2H),4.28-4.00 (m, 3H), 3.52-3.30 (m, 3H), 2.94-2.60 (m, 3H), 2.56-2.08 (m,10H), 1.74-1.32 (m, 5H).

EXAMPLE 11(c)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yltyrosinate trifluoroacetic acid salt

TLC: Rf 0.37 (Chloroform:Methanol=8:1); NMR(CD₃OD): δ 7.22-6.92 (m, 6H),6.77 (d, J=8.4 Hz, 2H), 5.69 (dd, J=15.3, 6.6 Hz, 1H), 5.36 (dd, J=15.3,8.7 Hz, 1H), 4.33 (m, 1H), 4.27-4.15 (m, 3H), 4.12 (m, 1H), 3.47 (m,1H), 3.16-3.04 (m, 2H), 2.96-2.06 (m, 13H), 1.80-1.48 (m, 5H).

EXAMPLE 12(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid isopropyloxycarbonylmethyl ester

To a solution of the compound prepared in Example 3(b) (31.5 mg) indimethylformamide (0.7 mL), 2-bromoacetic acid isopropyl ester (16.5 mg)and potassium carbonate (16 mg) was added, and the mixture was stirredfor 1.5 hours at 60° C. After cooling, the reaction mixture was added bywater and ethyl acetate. The organic layer was washed with water andbrine successively, dried over anhydrous sodium sulfate, concentratedunder reduced pressure and was purified by column chromatography onsilica gel (chloroform:methanol=50:1) to give the title compound (35 mg)having the following physical data.

TLC: Rf 0.45 (Chloroform:Methanol=9:1); NMR: δ 7.32-7.20 (m, 3H),7.14-7.06 (m, 1H), 5.74 (dd, J=15.3, 6.0 Hz, 1H), 5.50 (dd, J=15.3, 8.6Hz, 1H), 5.06 (m, 1H), 4.57 (s, 2H), 4.40 (m, 1H), 4.12 (m, 1H), 3.62(m, 1H), 2.96 (m, 1H), 2.82 (d, J=6.0 Hz, 2H), 2.71-2.50 (m, 6H),2.41-2.19 (m, 3H), 2.00-1.90 (m, 2H), 1.73 (m, 1H), 1.25 (d, J=6.3 Hz,6H).

EXAMPLE 12(a) to EXAMPLE 12(c)

By the same procedure as describe in Example 12 using the compoundprepared in Example 3(b) or corresponding carboxylic acid derivativesand corresponding halide derivatives instead of 2-bromoacetic acidisopropyl ester, the compound of the present invention having thefollowing physical data were obtained.

EXAMPLE 12(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid dimethylaminocarbonylmethyl ester

TLC: Rf 0.35 (Chloroform:Methanol=9:1); NMR: δ 7.28-7.19 (m, 3H),7.12-7.08 (m, 1H), 5.77 (dd, J=15.3, 5.1 Hz, 1H), 5.54 (ddd, J=15.3,8.7, 1.2 Hz, 1H), 4.70 (s, 2H), 4.40 (m, 1H), 4.15 (m, 1H), 3.54 (m,1H), 3.04 (m, 1H), 2.95 (s, 3H), 2.91 (s, 3H), 2.82 (d, J=6.0 Hz, 2H),2.78-2.53 (m, 6H), 2.40-2.18 (m, 3H), 2.03-1.93 (m, 2H), 1.71 (m, 1H).

EXAMPLE 12(b)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid ethyl ester

TLC: Rf 0.44 (Chloroform:Methanol=9:1); NMR: δ 7.21-7.14 (m, 2H),7.05-6.96 (m, 2H), 5.75 (dd, J=15.6, 6.0 Hz, 1H), 5.50 (dd, J=15.6, 8.4Hz, 1H), 4.19 (m, 1H), 4.18-4.03 (m, 3H), 3.60 (m, 1H), 2.97 (m, 1H),2.85-2.79 (m, 2H), 2.70-2.18 (m, 9H), 2.01-1.82 (m, 3H), 1.79-1.60 (m,1H), 1.25 (t, J=7.2 Hz,. 3H).

EXAMPLE 12(c)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid butyl ester

TLC: Rf 0.47 (Ethyl Acetate:Methanol=20:1); NMR: δ 7.2-7.1 (m, 2H),7.05-6.95 (m, 2H), 5.75 (dd, J=15,6Hz, 1H), 5.51 (dd, J=15, 8 Hz, 1H),4.45-4.35 (m, 1H), 4.15-4.05 (m, 1H), 4.07 (t, J=7 Hz, 2H), 3.7-3.55 (m,1H), 3.05-2.9 (m, 1H), 2.82 (d, J=7 Hz, 2H), 2.7-2.45 (m, 4H), 2.4-2.3(m, 4H), 2.3-2.15 (m, 1H), 2.0 (d, J=4 Hz, 1H), 1.95-1.85 (m, 2H),1.8-1.65 (m, 1H), 1.65-1.55 (m, 2H), 1.45-1.3 (m, 2H), 0.93 (t, J=7 Hz,3H).

REFERENCE EXAMPLE 17(15α,13E)-9-Oxo-15-(tetrahydropyran-2-yloxy)-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoicacid methyl ester

To a solution of(15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoicacid methyl ester (111 mg; this is the methyl ester of the compoundprepared in Example 2(ww)) in toluene (2 mL), dihydropyran (0.5 mL) andp-toluenesulfonic acid (1 mg) was added, and the mixture was stirred for6 hours at room temperature. The mixture was added by water and ethylacetate. The organic layer was washed with water and brine successively,dried over anhydrous sodium sulfate, concentrated under reduced pressureto give the title compound (146 mg) having the following physical data.

REFERENCE EXAMPLE 18(15α,13E)-9-Oxo-15-(tetrahydropyran-2-yloxy)-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-ol

To a solution of the compound prepared in Reference Example 17 (146 mg)in tetrahydrofuran (2.5 mL), lithium borohydride (62 mg) was added, andthe mixture was stirred for 7 hours at 50° C. The mixture was added bywater and ethyl acetate. The organic layer was washed with water andbrine successively, dried over an anhydrous sodium sulfate, concentratedunder reduced to give the title compound (101 mg) having the followingphysical data.

REFERENCES EXAMPLE 19(15α,13E)-9-Oxo-15-(tetrahydropyran-2-yloxy)-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-al

Under atmosphere of argon, a solution of the compound prepared inReference Example 18 (100 mg) in mixed solvent of ethyl acetate (1 mL)and dimethylsulfoxide (1.5 mL) was added by diisopropylethylamine (0.22mL). Then sulfur trioxide pyridine complex (100 mg) was added to themixture on ice bath, and the mixture was stirred for 15 minutes. Waterand ethyl acetatewere added to the reaction mixture. The organic layerwas washed with 1N hydrochloric acid, saturated aqueous sodiumhydrogencarbonate and brine successively, dried over an anhydrous sodiumsulfate, concentrated under reduced pressure to give the title compound(103 mg) having the following physical data.

TLC: Rf 0.51 (Ethyl Acetate).

EXAMPLE 13(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-1),5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-al

To a solution of the compound prepared in Reference Example 19 (100 mg)in mixed solvent of acetonitrile (1 mL) and methanol (0.5 mL), 0.1Nhydrochloric acid was added, and the mixture was stirred for 1 hour at35° C. Water and ethyl acetate were added to the reaction mixture. Theorganic layer was washed with saturated aqueous sodium hydrogencarbonateand brine successively, dried over an anhydrous sodium sulfate,concentrated under reduced pressure and was purified by columnchromatography on silica gel (from ethyl acetate:hexane=4:1 to ethylacetate only) to give the title compound (70 mg) having the followingphysical data.

TLC: Rf 0.34 (Ethyl Acetate); NMR: δ 9.80 (s, 1H), 7.60 (d, J=3.9 Hz,1H), 7.20 (t, J=7.4 Hz, 1H), 7.08-6.96 (m, 3H), 6.93 (d, J=3.9 Hz, 1H),5.73 (dd, J=15.4, 5.8 Hz, 1H), 5.48 (ddd, J=15.4, 8.8, 1.4 Hz, 1H), 4.39(m, 1H), 4.02 (m, 1H), 3.52 (m, 1H), 2.90-2.77 (m, 5H), 2.47-2.25 (m,2H), 2.36 (s, 3H), 2.20 (m, 1H), 1.88-1.64 (m, 3H).

EXAMPLE 13(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-al

By the same procedure as describe in Reference Examples 17, 18, 19 andExample 13 using the methyl ester of the compound prepared in Example3(b) instead of the methyl ester of compound prepared in Example 2(ww),the compound of the present invention having the following physical datawere obtained.

TLC: Rf 0.13 (Hexane:Ethyl Acetate=1:5); NMR: δ 9.80 (t, J=1.5 Hz, 1H),7.27-7.20 (m, 3H), 7.09 (m, 1H), 5.75 (dd, JΔ15.6, 5.4 Hz, 1H), 5.51(ddd, J=15.6, 8.7, 1.2 Hz, 1H), 4.43 (m, 1H), 4.09 (m, 1H), 3.60 (m,1H), 2.95 (m, 1H), 2.84 (d, J=6.6 Hz, 2H), 2.70-2.20 (m, 9H), 2.00-1.60(m, 3H).

EXAMPLE 14(15α,13E)-9-Oxo-15-hydroxy-16-(3-aminophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

The solution of(15α,13E)-9-oxo-15-hydroxy-16-(3-nitrophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid butyl ester (90 mg, this compound was prepared by the sameprocedure as describe in Reference Example 5 and Example 1 using9-oxo-12-formyl-13,14,15,16,17,18,19,20-octanor-5-thia-8-azaprostanoicacid butyl ester instead of the compound prepared in Reference Example 4and 3-(3-nitrophenyl)-2-oxopropylphosphonic acid dimethyl ester insteadof 3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl ester)of mixed solvent of methanol (1.4 mL), tetrahydrofuran (0.9 mL), water(0.45 mL) and acetic acid (0.27 mL) was added by Zinc powder (37 mg)under atmosphere of argon, and the mixture was stirred for 30 minutes atroom temperature. Water and ethyl acetate were added to the reactionmixture. The organic layer was washed with saturated aqueous sodiumhydrogencarbonate and brine successively, dried over an anhydrous sodiumsulfate, concentrated under reduced pressure and was purified by columnchromatography on silica gel (chloroform:methanol=100:1) and prepared bythe same procedure as describe in Example 2 to give the title compound(44 mg) having the following physical data.

TLC: Rf 0.46 (Chloroform:Methanol=9:1); NMR: δ 7.15-7.04 (m, 1H),6.64-6.50 (m, 3H), 5.75 (dd, J=15.0, 6.0 Hz, 1H), 5.50 (dd, J=15.0, 8.4Hz, 1H), 4.40 (m, 1H), 4.10 (m, 1H), 4.00-3.55 (m, 4H), 2.99 (m, 1H),2.80-2.19 (m, 11H), 1.98-1.80 (m, 2H), 1.78-1.61 (m, 1H).

EXAMPLE 15(a) to EXAMPLE 15(c)

By the same procedure as describe in Reference Example 16 and Example 10using(15α,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-olinstead of(15α,13E)-9-oxo-15-t-butyldimethylsilyloxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-oland corresponding carboxylic acid derivatives instead oft-butoxycarbonylglycilglycine, the compound of the present inventionhaving the following physical data were obtained.

The compound prepared in Example 15(c) was done by additional procedureof the same as described in Example 11.

EXAMPLE 15(a)(15α,13E)-1-Benzoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene

TLC: Rf 0.50 (Chloroform:Methanol=10:1); NMR: δ 8.05-8.02 (m, 2H), 7.55(m, 1H), 7.46-7.41 (m, 2H), 7.34-7.18 (m, 5H), 5.73 (dd, J=15.3, 6.0 Hz,1H1), 5.49 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.40 (m, 1H), 4.31 (t, J=6.6Hz,. 2H), 4.02 (m, 1H), 3.48 (m, 1H), 2.85 (d, J=6.6 Hz, 2H), 2.68 (m,1H), 2.45-2.10 (m, 3H), 1.80-1.20 (m, 11H).

EXAMPLE 15(b)(15α,13E)-1-Butanoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene

TLC: Rf 0.41 (Chloroform:Methanol=10:1); NMR: δ 7.34-7.19 (m, 5H), 5.73(dd, J=15.3, 6.3 Hz, 1H), 5.49 (ddd, J=15.3, 8.4, 1.2 Hz, 1H), 4.41 (m,1H), 4.05 (t, J=6.6 Hz, 2H), 4.03 (m, 1H), 3.47 (m, 1H), 2.85 (d, J=6.6Hz, 2H), 2.68 (m, 1H), 2.45-2.10 (m, 5H), 1.80-1.20 (m, 13H), 0.95 (t,J=7.2 Hz, 3H).

EXAMPLE 15(c)(15α,13E)-1-(2-Aminoacetyloxy)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enetrifluoromethanesulfonic acid salt

TLC: Rf 0.10 (Chloroform:Methanol=10:1); NMR: δ 7.32-7.17 (m, 5H), 5.72(dd, J=15.6, 6.3 Hz, 1H), 5.45 (dd, J=15.6, 8.7 Hz, 1H), 4.39 (m, 1H),4.19 (t, J=6.3 Hz, 2H), 4.01 (m, 1H), 3.77 (br, 2H), 3.39 (m, 1H),2.91-2.78 (m, 2H), 2.66 (m, 1H), 2.40-2.10 (m, 3H), 1.75-1.15 (m, I1H).

EXAMPLE 16(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-pentanoyloxyethyl ester

A solution of the compound prepared in Example 3(1) (100 mg),2-pentanoyloxyethanol (370 mg) and triethylamine (0.071 mL) in ethylacetate (1.3 mL) was stirred for 5 minutes. The reaction mixture wasadded by 1-methanesulfonyloxybenzotriazole (65 mg), and the mixture wasstirred for 3 hours at room temperature. The reaction mixture was addedby water, and was extracted by ethyl acetate. The extract was washedwith water, saturated aqueous sodium hydrogencarbonate and brinesuccessively, dried over an anhydrous sodium sulfate, concentrated underreduced pressure and was purified by column chromatography on silica gel(from ethyl acetate:hexane=3:1 to ethyl acetate only) to give the titlecompound (110 mg) having the following physical data.

TLC: Rf 0.33 (Ethyl Acetate); NMR: δ 7.23-7.15 (m, 2H), 7.06-6.97 (m,2H), 5.76 (dd, J=15.0, 5.4 Hz, 1H), 5.50 (dd, J=15.0, 8.7 Hz, 1H), 4.40(m, 1H), 4.27 (s, 4H), 4.10 (m, 1H), 3.60 (m, 1H), 2.98 (m, 1H), 2.82(d, J=6.0 Hz, 2H), 2.68-2.20 (m, 11H), 1.96-1.83 (m, 3H), 1.78-1.57 (m,3H), 1.41-1.29 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 16(a) to EXAMPLE 16(k)

By the same procedure as describe in Example 16 using the compoundprepared in Example 3 or corresponding carboxylic acid derivatives andcorresponding alcohol derivatives instead of 2-pentanoyloxyethanol, thecompound of the present invention having the following physical datawere obtained.

EXAMPLE 16(a)(15α,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoicacid 4-phenylbenzyl ester

TLC: Rf 0.57 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.63-7.56 (m,4H), 7.48-7.18 (m, 1OH), 5.71 (dd, J=15.4, 5.8 Hz, 1H), 5.46 (ddd,J=15.4, 8.2, 1.1 Hz, 1H), 5.17 (s, 2H), 4.40 (m, 1H), 3.99 (m, 1H), 3.44(m, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.66 (m, 1H), 2.40-2.31 (m, 4H), 2.20(m, 1H), 1.70-1.61 (m, 3H), 1.50-1.20 (m, 6H).

EXAMPLE 16(b)(15α,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoicacid 3-phenylphenyl ester

TLC: Rf 0.48 (Hexane:Ethyl Acetate=1:3); NMR: δ 7.61-7.55 (m, 2H),7.48-7.17 (m, 11H), 7.05 (m, 1H), 5.72 (dd, J=15.4, 5.8 Hz, 1H), 5.48(ddd, J=15.4, 8.5, 1.1 Hz, 1H), 4.40 (m, 1H), 4.02 (m, 1H), 3.48 (m,1H), 2.83 (d, J=6.6 Hz, 2H), 2.72 ( m, 1H), 2.59 (t, J=7.4 Hz, 2H),2.41-2.34 (m, 2H), 2.21 (m, 1H), 1.81-1.62 (m, 3H), 1.54-1.22 (m, 6H).

EXAMPLE 16(c)(15α,13E)-9-Oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoicacid 2-dimethylaminoethyl ester hydrochloride

TLC: Rf 0.39 (Chloroform:Methanol=9:1); NMR(CD₃OD): δ 7.30-7.12 (m, 5H),5.68 (dd, J=15.3, 6.6 Hz, 1H), 5.36 (dd, J=15.3, 9.0 Hz, 1H), 4.43-4.29(m, 3H), 4.07 (m, 1H), 3.45 (m, 2H), 3.38-3.20 (m, 1H), 2.94-2.89 (m,7H), 2.72 (m, 1H), 2.54 (m, 1H), 2.44-2.17 (m, 5H), 1.76-1.56 (m, 3H),1.55-1.18 (m, 6H).

EXAMPLE 16(d)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-hexanoyloxyethyl ester

TLC: Rf 0.27 (Ethyl Acetate); NMR: δ 7.21-7.12 (m, 2H), 7.07-6.97 (m,2H), 5.75 (dd, J=15.0, 6.0 Hz, 1H), 5.51 (dd, J=15.0, 8.6 Hz, 1H), 4.39(m, 1H), 4.27 (s, 4H), 4.10 (m, 1H), 3.61 (m, 1H), 2.96 (m, 1H), 2.82(d, J=6.6 Hz, 2H), 2.70-2.14 (m, 11H), 1.99-1.82 (m, 3H), 1.79-1.55 (m,2H), 1.40-1.22 (m, 4H), 0.90 (t, J=7.0 Hz, 3H).

EXAMPLE 16(e)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-heptanoyloxyethyl ester

TLC: Rf 0.29 (Ethyl Acetate); NMR: δ 7.21-7.13 (m, 2H), 7.06-6.97 (m,2H), 5.75 (dd, J=15.0, 6.0 Hz, 1H), 5.50 (dd, J=15.0, 8.4 Hz, 1H), 4.39(m, 1H), 4.27 (s, 4H), 4.10 (m, 1H), 3.61 (m, 1H), 2.97 (m, 1H), 2.82(d, J=6.6 Hz, 2H), 2.68-2.16 (m, 11H), 1.97-1.83 (m, 3H), 1.76-1.55 (m,2H), 1.40-1.20 (m, 6H), 0.89 (t, J=7.0 Hz, 3H).

EXAMPLE 16(f)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-octanoyloxyethyl ester

TLC: Rf 0.26 (Ethyl Acetate:Methanol=20:1); NMR: δ 7.22-7.12 (m, 2H),7.07-6.97 (m, 2H), 5.75 (dd, J=15.3, 5.4 Hz, 1H), 5.51 (dd, J=15.3, 8.4Hz, 1H), 4.45-4.36 (m, 1H), 4.26 (s, 4H), 4.18-4.07 (m, 1H), 3.70-3.57(m, 1H), 3.02-2.90 (m, 1H), 2.82 (d, J=5.4 Hz, 2H), 2.70-2.50 (m, 4H),2.45 (t, J=7.2 Hz, 2H), 2.40-2.18 (m, 5H), 1.98-1.86 (m, 3H), 1.80-1.50(m, 3H), 1.40-1.20 (m, 8H), 0.89 (t, J=7.2 Hz, 3H).

EXAMPLE 16(g)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid N-heptanoyl-N-methylcarbamoylmethyl ester

TLC: Rf 0.69 (Chloroform:Methanol=9:1); NMR: δ 7.21-7.14 (m, 2H),7.04-6.97 (m, 2H), 5.75 (ddd, J=15.0, 5.4, 1.2 Hz, 1H), 5.53 (dd, J=15.,8.7 Hz, 1H), 4.73-4.65 (m, 2H), 4.39 (m, 1H), 4.13 (m, 1H), 3.58 (m,1H), 3.39-3.24 (m, 1H), 3.20-3.10 (m, 1H), 3.06 (m, 1H), 2.93-2.77 (m,5H), 2.71-2.15 (m, 9H), 2.00-1.89 (m, 2H), 1.78-1.42 (m, 3H), 1.40-1.20(m, 8H), 0.95-0.82 (m, 3H).

EXAMPLE 16(h)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid (4-hexylpiperazin-1-yl)carbonylmethyl ester

TLC: Rf 0.71 (Chloroform:Methanol=9:1); NMR: δ 7.22-7.12 (m, 2H),7.06-6.96 (m, 2), 5.76 (dd, J=15.3, 5.4 Hz, 1H), 5.52 (dd, J=15.3, 8.7Hz, 1H), 4.70 (s, 2H), 4.43-4.35 (m, 1H), 4.18-4.07 (m, 1H), 3.70-3.50(m, 3H), 3.41-3.32 (m, 2H), 3.09-2.97 (m, 1H), 2.81 (d, J=6.6 Hz, 2H),2.72-2.5 (m, 6H), 2.5-2.2 (m, 9H), 2.01-1.89 (m, 2H), 1,80-1.58 (m, 1H),1.58-1.41 (m, 2H), 1.41-1.22 (m, 6H), 0.09 (t, J=7.2Hz, 3H).

EXAMPLE 16(i)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid N-ethyl-N-(2-diethylaminoethyl)carbamoylmethyl ester

TLC: Rf 0.29 (Chloroform:Methanol=9:1); NMR: δ 7.25-7.10 (m, 2H),7.05-6.95 (m, 2H), 5.76 (dd, J=15.0, 5.4 Hz, 1H), 5.60-5.45 (m, 1H),4.79 and 4.71 (s, 2H), 4.38 (q, J=6.0 Hz, 1H), 4.12 (q, J=7.2 Hz, 1H),3.65-3.50 (m, 1H), 3.45-3.20 (m, 4H), 3.10-2.95 (m, 1H), 2.82 (d, J=6.0Hz, 2H), 2.75-2.40 (m, 10H), 2.40-2.15 (m, 4H), 2.05-1.85 (m, 2H),1,80-1.60 (m, 1H), 1.22 and 1.12 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.2 Hz,3H), 1.04 (t, J=7.2 Hz, 3H).

EXAMPLE 16(I)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-(2-(dipropylamino)acetyloxy)ethyl ester

TLC: Rf 0.47 (Chloroform:Methanol=9:1); NMR: δ 7.21-7.15 (m, 2H),7.04-6.97 (m, 2H), 5,76 (dd, J=15.3, 5.7 Hz, 1H), 5.50 (ddd, J=15.3,8.4, 1.0 Hz, 1H), 4.40 (m, 1H), 4.37-4.20 (m, 4H), 4.10 (m, 1H), 3.60(m, 1H), 3.35 (s, 2H), 2.97 (m, 1H), 2.80 (d, J=6.0 Hz, 2H), 2.65-2.19(m, 13H), 1.97-1.84 (m, 3H), 1.78-1.40 (m, 5H), 0.88 (t, J=7.5 Hz, 6H).

EXAMPLE 16(k)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-(2-(diethylamino)acetyloxy)ethyl ester

TLC: Rf 0.46 (Chloroform:Methanol=9:1); NMR: δ 7.20-7.14 (m, 2H),7.06-6.95 (m, 2H), 5.75 (dd, J=15.3, 5.7 Hz, 1H), 5.50 (dd, J=15.3, 8.4Hz, 1H), 4.42-4.20 (m, 5H),4.10 (m, 1H), 3.60 (m, 1H), 3.34 (s, 2H),2.97 (m, 1H), 2.80 (d, J=7.0 Hz, 2H), 2.70-2.17 (m, 13H), 2.00-1.83 (m,3H), 1.70 (m, 1H), 1.06 (t, J=7.2 Hz, 6H).

EXAMPLE 17(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid nonanoyloxymethyl ester

By the same procedure as describe in Example 12 using the compoundprepared in Example 3(1) instead of the compound prepared in Example3(b) and nonanoyloxymethyl chloride instead of 2-bromoacetic acidisopropyl ester, the compound of the present invention having thefollowing physical data were obtained.

TLC: Rf 0.31 (Hexane:Ethyl Acetate=1:4); NMR: δ 17.21-7.12 (m, 2H),7.06-6.96 (m, 2H), 5.81-5.69 (m, 3H), 5.50 (dd, J=15.3, 8.4 Hz, 1H),4.39 (m, 1H), 4.10 (m, 1H), 3.61 (m, 1H), 3.00-2.78 (m, 3H), 2.69-2.17(m, 11H), 2.00-1.50 (m, 4H), 1.40-1.19 (m, 10H), 0.88 (t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 20(9α,11α,15α,13E)-9-Hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid

To a solution of(9α,11α,15α,13E)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid methyl ester (5 g; this is the compound described in ReferenceExample 28 of WO00/03980) in methanol (8 mL), 2N aqueous sodiumhydroxide (8.1 mL) was added, and the mixture was stirred for 1.5 hoursat room temperature. After cooling, 2N hydrochloric acid was added tothe aqueous layer to acidify, then the mixture was extracted by ethylacetate. The extract was washed with brine, dried over an anhydroussodium sulfate, concentrated under reduced pressure to give the titlecompound having the following physical data, which was used for the nextreaction without purification.

TLC: Rf 0.55 (Ethyl Acetate); NMR: δ 7.3-7.1 (m, 4H), 5.7-5.3 (m, 2H),4.8-3.1 (m, 9H), 3.5-3.1 (m, 5H), 3.0-2.0 (m, 10H), 2.0-1.3 (m, 18H).

REFERENCE EXAMPLE 21(9α,11α,15α,13E)-9-Hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-nonanoyloxyethyl ester

To a solution of the compound prepared in Reference Example 20 indimethylformamide (16 mL), nonanoic acid 2-bromoethylester (2.35 g),sodium iodide (121 mg) and potassium carbonate (1.67 g) were added, andthe mixture was stirred for 2 hours at 50° C. After cooling, the mixturewas added by water, and extracted by ethyl acetate. The extract waswashed with water and brine, dried over an anhydrous sodium sulfate,concentrated under reduced pressure and was purified by columnchromatography on silica gel (ethyl acetate:hexane=1:1) to give thetitle compound (6.33 g) having the following physical data.

TLC: Rf 0.43 (Hexane: Ethyl Acetate=1:1); NMR: δ 7.3-7.1 (m, 4H),5.7-5.3 (m, 2H), 4.75-4.45 (m, 2H), 4.42 (s, 2H), 4.27 (s, 4H), 4.3-3.7(m, 3H), 3.5-3.2 (m, 5H), 3.0-2.7 (m, 2H), 2.6-2.4 (m, 6H), 2.33 (t,J=7.2 Hz, 2H), 2.3-2.0 (m, 1H), 2.0-1.2 (m, 31H), 0.90 (t, J=7.2 Hz,3H).

REFERENCE EXAMPLE 22(11α,15α,13E)-9-Oxo-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-nonanoyloxyethyl ester

To a solution of the compound prepared in Reference Example 21 (6.33 g)in ethyl acetate (28 mL), diisopropylethylamine (8.35 mL) was added oniced bath. Then sulfur trioxide pyridine complex (3.82 g) anddimethylsulfoxide (14 mL) were added to the mixture, and the mixture wasstirred for 20 minutes. The reaction mixture was added by water and wasextracted by ethyl acetate. The extract was washed with water and brinesuccessively, dried over an anhydrous sodium sulfate, concentrated underreduced pressure and was purified by column chromatography on silica gel(ethyl acetate:hexane=1:1) to give the title compound (5.12 g) havingthe following physical data.

TLC: Rf 0.50 (Hexane:Ethyl Acetate=1:1); NMR: δ 7.3-7.1 (m, 4H),5.8-5.25 (m, 2H), 4.8-4.5 (m, 2H), 4.42 (s, 2H), 4.4-3.7 (m, 8H),3.55-3.2 (m, 5H), 3.0-2.65 (m, 3H), 2.65-2.4 (m, 7H), 2.4-2.05 (m, 4H),1.95-1.2 (m, 28H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 18(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-nonanoyloxyethyl ester

To a solution of the compound prepared in Reference Example 22 (5.12 g)in mixed solvent of methanol (26 mL), 1,2-dimethoxyethane (26 mL) andacetonitrile (26 mL), 0.1N hydrochloric acid (26 mL) was added, and themixture was stirred for 3 hours at 35° C. The reaction mixture was addedby water and was extracted by ethyl acetate. The extract was washed withsaturated aqueous sodium hydrogen carbonate solution and brinesuccessively, dried over an anhydrous magnesium sulfate, concentratedunder reduced pressure and was purified by column chromatography onsilica gel (ethyl acetate:hexane=from 3:1 to 4:1, then ethyl acetateonly) to give the title compound (2.71 g) having the following physicaldata.

TLC: Rf 0.33 (Ethyl Acetate); NMR: δ 7.30 (t, J=8.1 Hz, 1H), 7.23-7.11(m, 3H), 5.76 (dd, J=15.3,6.0Hz, 1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H),4.48-4.39 (m, 3H), 4.26 (s, 4H), 4.00-3.90 (m, 1H), 3.42 (s, 3H),3.15-3.08 (br, 1H), 2.91 (dd, J=13.5, 5.4 Hz, 1H), 2.83 (dd, J=13.5, 6.9Hz, 1H), 2.70 (dd, J=18.6, 7.5 Hz, 1H), 2.65-2.50 (m, 2H), 2.52 (t,J=7.2 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.2 Hz, 2H), 2.40-2.13(m, 4H), 1.95-1.82 (m, 3H), 1.74-1.60 (m, 3H), 1.40-1.20 (m, 10H), 0.89(t, J=7.2 Hz, 3H).

EXAMPLE 18(a) to EXAMPLE 18(q)

By the same procedure as describe in Reference Examples 21, 22 andExample 18 using corresponding halides instead of nonanoic acid2-bromoethyl ester, the compound of the present invention having thefollowing physical data were obtained.

EXAMPLE 18(a)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid pivaloyloxymethyl ester

TLC: Rf0.63 (Chloroform:Methanol=9:1); NMR: δ 7.33-7.10 (m, 4H), 5.74(s, 2H), 5.73 (dd, J=15, 6.0 Hz, 1H), 5.53 (ddd, J=15, 8.7 0.7 Hz, 1H),4.48-4.37 (m, 3H), 3.94 (m, 1H), 3.42 (s, 3H), 2.90 (dd, J=13, 5.6 Hz,1H), 2.83 (dd, J=13, 6.9 Hz, 1H), 2.70 (ddd, J=19, 7.5, 1.1 Hz, 1H),2.62-2.43 (m, 6H), 2.38-2.12 (m, 3H), 1.95-1.81 (m, 3H), 1.74-1.59 (m,1H), 1.21 (s, 9H).

EXAMPLE 18(b)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 1-cyclohexyloxycarbonyloxyethyl ester

TLC: Rf0.63 (Chloroform: Methanol=9:1); NMR: δ 7.33-7.09 (m, 4H), 6.75(q, J=5.4 Hz, 1H), 5.73 (dd, J=15, 6.3 Hz, 1H), 5.53 (dd, J=15, 8.6 Hz,1H), 4.63 (m, 1H), 4.48-4.34 (m, 3H), 3.94 (m, 1H), 3.41 (s, 3H), 2.88(J=14, 5.6 Hz, 1H), 2.82 (dd, J=14, 6.9 Hz, 1H), 2.69 (ddd, J=19, 7.6,1.0 Hz, 1H), 2.64-2.41 (m, 6H), 2.37-2.12 (m, 3H), 1.98-1.17 (m, 14H),1.51 (d, J=5.4 Hz, 3H).

EXAMPLE 18(c)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid N,N-diethylaminocarbonylmethyl ester

TLC: Rf0.18 (Ethyl Acetate:Methanol=50:1); NMR: δ 7.3-7.1 (m, 4H), 5.76(dd, J=15, 6 Hz, 1H), 5.55 (dd, J=15, 8 Hz, 1H), 4.70 (s, 2H), 4.42 (s,2H), 4.5-4.4 (m, 1H), 3.90 (q, J=8 Hz, 1H), 3.41 (s, 3H), 3.37 (q, J=7Hz, 2 H), 3.24 (q, J=7 Hz, 2 H), 2.95-2.8 (m, 2H), 2.69 (dd, J=18, 7 Hz,1H), 2.65-2.5 (m, 6H), 2.4-2.1 (m, 4H), 2.4-1.8 (m, br), 2.0-1.8 (m,2H), 1.75-1.6 (m, 1H), 1.22 (t, J=7 Hz, 3H), 1.15 (t, J=7 Hz, 3H).

EXAMPLE 18(d)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-acetyloxyethyl ester

TLC: Rf0.28 (Ethyl Acetate); NMR: δ 7.3-7.1 (m, 4H), 5.76 (dd, J=15, 6Hz, 1H), 5.53 (dd, J=15, 8 Hz, 1H), 4.5-4.4 (m, 3H), 4.27 (s, 4H), 3.94(brq, 1H), 3.42 (s, 3H), 3.05-3.0 (br, 1H), 2.91 (dd, J=14, 6 Hz, 1H),2.83 (dd, J=14, 7 Hz, 1H), 2.70 (dd, J=18, 7 Hz, 1H), 2.65-2.5 (m, 2H),2.51 (t, J=7 Hz, 2H), 2.45 (t, J=7 Hz, 2H), 2.4-2.1 (m, 4H), 2.08 (s,3H), 1.95-1.8 (m, 3H), 1.8-1.6 (m, 1H).

EXAMPLE 18(e)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid benzoylmethyl ester

TLC: Rf0.32 (Ethyl Acetate); NMR: δ 7.92-7.88 (m, 2H), 7.65-7.59 (m,1H), 7.52-7.46 (m, 2H), 7.34-7.10 (m, 4H), 5.77 (dd, J=15.6, 5.7 Hz,1H), 5.54 (dd, J=15.6, 8.4 Hz, 1H), 5.35 (s, 2H), 4.50-4.38 (m, 3H),4.00-3.89 (m, 1H), 3.41 (s, 3H), 2.87-2.54 (m, 9H), 2.41-2.18 (m, 3H),2.04-1.84 (m, 3H), 1.78-1.65 (m, 1H).

EXAMPLE 18(f)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid isopropyloxycarbonylmethyl ester

TLC: Rf0.30 (Ethyl Acetate); NMR: δ 7.35-7.12 (m, 4H), 5.75 (dd, J=15.0,5.7 Hz, 1H), 5.53 (dd, J=15.0, 8.4 Hz, 1H), 5.07 (m, 1H), 4.56 (s, 2H),4.47-4.37 (m, 3H), 3.93 (m, 1H), 3.42 (s, 3H), 3.05-2.50 (m, 10H),2.39-2.14 (m, 4H), 1.98-1.83 (m, 3H), 1.78-1.60 (m, 1H), 1.25 (d, J=6.3Hz, 6H).

EXAMPLE 18(g)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid N,N-diethylaminocarbonyloxymethyl ester

TLC: Rf0.34 (Ethyl Acetate); NMR: δ 7.3-7.1 (m, 4H), 5.76 (s, 2H), 5.75(dd, J=15, 6 Hz, 1H), 5.53 (dd, J=15, 8 Hz, 1H), 4.5-4.35 (m, 3H), 3.93(brq, 1H), 3.42 (s, 3H), 3.4-3.2 (m, 4H), 2.95-2.8 (m, 2H), 2.70 (dd,J=19, 8 Hz, 1H), 2.65-2.45 (m, 6H), 2.4-2.1 (m, 4H), 1.95-1.8 (m, 4H),1.75-1.6 (m, 1H), 1.2-1.05 (m, 6H).

EXAMPLE 18(h)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid t-butyloxycarbonylmethyl ester

TLC: Rf0.36 (Ethyl Acetate); NMR: δ 7.35-7.12 (m, 4H), 5.73 (dd, J=15.0,6.0 Hz, 1H), 5.51 (dd, J=15.0, 8.0 Hz, 1H), 4.50 (s, 2H), 4.43-4.35 (m,3H), 3.99-3.88 (m, 1H), 3.42-3.20 (m, 4H), 2.89-2.15 (m, 11H), 1.95-1.60(m, 6H), 1.47 (s, 9H).

EXAMPLE 18(i)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 1-isopropyloxycarbonylethyl ester

TLC: Rf0.44 (Ethyl Acetate); NMR: δ 7.36-7.12 (m, 4H), 5.76 (dd, J=15.0,5.4 Hz, 1H), 5.53 (dd, J=15.0, 8.4 Hz, 1H), 5.10-4.97 (m, 1H), 4.47-4.38(m, 3H), 3.99-3.87 (m, 1H), 3.42 (s, 3H), 2.97-2.14 (m, 12H), 1.97-1.61(m, 7H), 1.46 (d, J=7.2 Hz, 3H), 1.27 and 1.23 (d, J=7.0 Hz, 6H)

EXAMPLE 18(j)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 1-benzoylethyl ester

TLC: Rf0.37 (Ethyl Acetate); NMR: δ 7.92 (d, J=8.4 Hz, 2H), 7.63-7.57(m, 1H), 7.51-7.44 (m, 2H), 7.31-7.25 (m, 1H), 7.19-7.10 (m, 3H), 5.95(q, J=7.20 Hz, 1H), 5.74 (ddd, J=15.3, 5.7, 4.2 Hz, 1H), 5.52 (ddd,J=15.3, 7.5, 1.8 Hz, 1H), 4.47-4.35 (m, 3H), 4.09-3.94 (m, 1H), 3.41 (s,3H), 3.02-2.13 (m, 14H), 1.97-1.65 (m, 4H), 1.52 (d, J=7.2 Hz, 3H).

EXAMPLE 18(k)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid methoxycarbonylmethyl ester

TLC : Rf0.36 (Chloroform:Methanol=10:1); NMR: δ 7.32-7.15 (m, 4H), 5.74(dd, J=15.3, 6.3 Hz, 1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.62 (s, 2H),4.42 (m, 2H), 4.39 (m, 1H), 3.94 (m, 1H), 3.76 (s, 3H), 3.41 (s, 3),3.24 (brs, 1H), 2.91-2.51 (m, 8H), 2.41-2.14 (m, 4H), 1.95-1.83 (m, 3H),1.74-1.62 (m, 2H).

EXAMPLE 18(l)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-tridecanoyloxyethyl ester

TLC: Rf0.36 (Ethyl Acetate); NM: δ7.3-7.1 (m, 4H), 5.77 (dd, J=15, 6 Hz,1H), 5.53 (dd, J=15, 8Hz, 1H), 4.5-4.4 (m, 3H), 4.25 (s, 4H), 4.0-3.9(brq, 1H), 3.42 (s, 3H), 2.92 (dd, J=14, 5 Hz, 1H), 2.84 (dd, J=14, 7Hz, 1H), 2.70 (dd, J=19, 8 Hz, 1H), 2.65-2.5 (m, 2H), 2.50 (t, J=7 Hz,2H), 2.45 (t, J=7 Hz, 2H), 2.33 (t, J=7 Hz, 2H), 2.4-2.1 (m, 5H),1.95-1.8 (m, 3H), 1.75-1.5 (m, 3H), 1.4-1.2 (m, 18H), 0.87 (t, J=7 Hz,3H).

EXAMPLE 18(m)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-heptanoyloxyethyl ester

TLC: Rf0.35 (Ethyl Acetate); NMR: δ 7.3-7.1 (m, 4H), 5.74 (dd, J=15, 6Hz, 1H), 5.52 (dd, J=15, 8Hz, 1H), 4.5-4.3 (m, 3H), 4.26 (s, 4H),4.0-3.9 (m, 1H), 3.42 (s, 3H), 3.35-3.3 (br, 1H), 2.89 (dd, J=14, 6 Hz,1H), 2.81 (dd, J=1 4, 7Hz, 1H), 2.70 (dd, J=19, 8 Hz, 1H), 2.65-2.5 (m,2H), 2.52 (t, J=7 Hz, 2H), 2.47 (t, J=7 Hz, 2H), 2.5-2.4 (br, 1H),2.4-2.15 (m, 5H), 1.95-1.8 (m, 3H), 1.75-1.55 (m, 3H), 1.4-1.2 (m, 6H),0.90 (t, J=7 Hz, 3H).

EXAMPLE 18(n)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-octanoyloxyethyl ester

TLC: Rf0.22 (Hexane:Ethyl Acetate=1:1); NMR: δ 7.35-7.10 (m, 4H), 5.76(dd, J=15.3, 5.7 Hz, 1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.38 (m,3H), 4.27 (s, 4H), 3.96 (m, 1H), 3.42 (s, 3H), 3.00-2.80 (m, 3H),2.78-2.40 (m, 7H), 2.39-2.13 (m, 6H), 1.96-1.80 (m, 3H), 1.78-1.57 (m,3H), 1.40-1.20 (m, 8H), 0.88 (t, J=7.0 Hz, 3H).

EXAMPLE 18(o)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-decanoyloxyethyl ester

TLC: Rf0.23 (Hexane:Ethyl Acetate=1:1); NMR: δ 7.36-7.12 (m, 4H), 5.76(dd, J=15.0, 6.0 Hz, 1H), 5.53 (dd, J=15.0, 8.0 Hz, 1H), 4.44-4.39 (m,3H), 4.27 (s, 4H), 3.96 (m, 1H), 3.42 (s, 3H), 2.99-2.80 (m, 3H),2.78-2.40 (m, 7H), 2.39-2.12 (m, 6H), 1.95-1.80 (m, 3H), 1.77-1.60 (m,3H), 1.39-1.19 (m, 12H), 0.88 (t, J=6.9 Hz, 3H).

EXAMPLE 18(p)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid allyloxycarbonylmethyl ester

TLC: Rf0.58 (Ethyl Acetate); NMR: δ 7.4-7.1 (m, 4H), 6.0-5.8 (m, 1H),5.78 (dd, J=16, 6 Hz, 1H), 5.53 (dd, J=16, 8 Hz, 1H), 5.4-5.25 (m, 2H),4.7-4.6 (m, 4H), 4.5-4.4 (m, 3H), 4.0-3.85 (m, 1H), 3.42 (s, 3H),3.0-2.8 (m, 2H), 2.72 (dd, J=19, 10 Hz, 1H), 2.65-2.5 (m, 6H), 2.4-2.1(m, 4H), 2.0-1.6 (m, 5H).

EXAMPLE 18(g)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid nonanoyloxymethyl ester

TLC: Rf0.25 (Hexane:Ethyl Acetate=1:4); NMR: δ 7.35-7.10 (m, 4H),5.81-5.69 (m, 3H), 5.52 (dd, J=15.0, 8.7 Hz, 1H), 4.48-4.37 (m, 3H),3.95 (m, 1H), 3.42 (s, 3H), 3.10 (bs, 1H), 2.92-2.42 (m, 9H), 2.40-2.11(m, 6H), 1.97-1.80 (m, 3H), 1.78-1.58 (m, 3H), 1.40-1.20 (m, 10H), 0.88(t, J=7.2 Hz, 3H).

REFERENCE EXAMPLE 23(11α,15α,13E)-9-Oxo-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-(tetrahydropyran-2-yloxy)ethyl ester

By the same procedure as describe in Reference Examples 21 and 22 using1-(tetrahydropyran-2-yloxy)-2-bromoethane instead of nonanoic acid2-bromoethyl ester, the title compound having the following physicaldata were obtained.

TLC: Rf0.51 (Hexane:Ethyl Acetate=1:1).

EXAMPLE 19(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-hydroxyethyl ester

By the same procedure as describe in Example 18 using the compoundprepared in Reference Example 23 instead of the compound prepared inReference Example 22, the compound of the present invention having thefollowing physical data were obtained

TLC: Rf0.35 (Ethyl Acetate:Methanol=19:1); NMR: δ 7.32-7.11 (m, 4H),5.77 (dd, J=15.3, 5.7 Hz, 1H), 5.54 (dd, J=15.3, 8.1 Hz, 1H), 4.48-4.38(m, 3H), 4.22-4.17 (m, 2H), 4.00-3.90 (m, 1H), 3.82-3.75 (m, 2H), 3.42(s, 3H), 3.12-2.91 (br, 1H), 2.92 (dd, J=13.5, 5.4 Hz, 1H), 2.84 (dd,J=13.5, 6.9 Hz, 1H), 2.71 (dd, J=18.9, 7.5 Hz, 1H), 2.65-2.50 (m, 2H),2.52 (t, J=7.2 Hz, 2H), 2.47 (t, J=7.2 Hz, 2H), 2.45-2.15 (m, 5H),1.95-1.80 (m, 3H), 1.76-1.60 (m, 1H).

REFERENCE EXAMPLE 24(9α,11α,15α,13E)-9-Trimethylsilyloxy-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid

Under atmosphere of argon, a solution of the compound prepared inReference Example 20 (680 mg) in dry tetrahydrofuran (5 mL),triethylamine (0.94 mL), and trimethylsilyl chloride (0.57 mL) andcatalytic amount of dimethylaminopyridine was added successively at roomtemperature, and the mixture was stirred for 5 hour at room temperature.The reaction mixture was added by water, and was extracted by ethylacetate. The extract was washed with brine, dried over an anhydroussodium sulfate, concentrated under reduced pressure to give the titlecompound having the following physical data, which was used for the nextreaction without purification.

TLC: Rf0.45 (Ethyl Acetate).

REFERENCE EXAMPLE 25(9α,11α,15α,13E)-9-Hydroxy-11,15-bis(tetrahydropyran-2-yloxy)-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid phenyl ester

To a solution of the compound prepared in Reference Example 24,triethylamine (0.15 mL) and phenol (53 mg) in acetonitrile (3 mL),1-hydroxybenzotriazole (50 mg) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydyochloride (142 mg)was added under atmosphere of argon at room temperature, and the mixturewas stirred for 2 hours at room temperature. The reaction mixture wasadded by ethyl acetate, was washed with 1N hydrochloric acid (twice),water, saturated aqueous sodium hydrogen carbonate solution and brinesuccessively, dried over an anhydrous sodium sulfate, concentrated underreduced pressure and was purified by column chromatography on silica gel(ethyl acetate: hexane=1:1) to give the title compound (115 mg) havingthe following physical data.

TLC: Rf0.35 (Hexane:Ethyl Acetate=1:1).

EXAMPLE 20(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid phenyl ester

By the same procedure as describe in Reference Example 22 and Example 18using the compound prepared in Reference Example 25 instead of thecompound prepared in Reference Example 21, the compound of the presentinvention having the following physical data were obtained

TLC: Rf0.34 (Ethyl Acetate); NMR: δ 7.4-7.0 (m, 9H), 5.74 (dd, J=15, 6Hz, 1H), 5.51 (dd, J=15, 8 Hz, 1H), 4.5-4.3 (m, 3H), 3.93 (brq, 1H),3.42 (s, 3H), 3.2-3.1 (br, 1H), 2.88 (dd, J=14, 6 Hz, 1H), 2.80 (dd,J=14, 7 Hz, 1H), 2.75-2.5 (m, 7H), 2.4-2.1 (m, 4H), 2.1-1.95 (m, 2H),2.0-1.85 (m, 1H), 1.8-1.6 (m, 1H).

EXAMPLE 21(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid carboxymethyl ester

To a solution of the compound prepared in Example 18(p) in drytetrahydrofuran (1.5 mL), tetrakis(triphenylphosphine)palladium(0) (15mg) was added under atmosphere of argon. The morpholine (68 μL) wasdropped into the mixture, and the mixture was stirred for 30 minutes atroom temperature. The reaction mixture was added by ethyl acetate, waswashed with 1N hydrochloric acid, water, saturated aqueous sodiumhydrogen carbonate solution and brine successively, dried over ananhydrous sodium sulfate, concentrated under reduced pressure and waspurified by column chromatography on silica gel (ethyl acetate aceticacid=100:1) to give the title compound (52 mg) having the followingphysical data.

TLC: Rf0.30 (Chloroform:Methanol:Acetic Acid=45:5:1); NMR: δ 7.3-7.1 (m,4H), 5.80 (dd, J=15, 6 Hz, 1H), 5.57 (dd, J=15, 8 Hz, 1H), 4.58 (s, 2H),4.47 (s, 2H), 4.5-4.4 (m, 1H), 4.0-3.9 (m, 1H), 3.23 (s, 3H), 2.93 (dd,J=14, 5 Hz, 1H), 2.81 (dd, J=14, 7 Hz, 1H), 2.8-2.5 (m, 7H), 2.5-2.2 (m,3H), 2.0-1.8 (m, 3H), 1.8-1.65 (m, 1H).

EXAMPLE 22(a) TO EXAMPLE 22(e)

By the same procedure as describe in Reference Examples 21, 22 andExample 18 using corresponding halides instead of nonanoic acid2-bromoethyl ester, the compound of the present invention having thefollowing physical data were obtained.

EXAMPLE 22(a)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid dipropylcarbamoylmethyl ester

TLC: Rf0.32 (Ethyl Acetate); NMR: δ 7.32-7.27 (m, 1H), 7.22-7.13 (m,3H), 5.74 (dd, J=15.9, 6.3 Hz, 1H), 5.54 (ddd, J=15.9, 8.4, 1.2 Hz, 1H),4.71 (s, 2H), 4.42 (m, 3H), 3.94 (m, 1H), 3.41 (s, 3H), 3.28 (m, 2H),3.19-3.08 (m, 3H), 2.95-2.80 (m, 2H), 2.78-2.50 (m, 8H), 2.40-2.18 (m,3H), 2.00-1.83 (m, 3H), 1.76-1.50 (m, 5H), 0.94 (t, J=7.5 Hz, 3H), 0.88(t, J=7.5 Hz, 3H).

EXAMPLE 22(b)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid dibutylcarbamoylmethyl ester

TLC: Rf0.36 (Ethyl Acetate); NMR: δ 7.32-7.26 (m, 1H), 7.22-7.13 (m,3H), 5.74 (dd, J=15.6, 6.0 Hz, 1H), 5.54 (dd, J=15.6, 8.4 Hz, 1H), 4.71(s, 2H), 4.42 (m, 3H), 3.94 (m, 1H), 3.41 (s, 3H), 3.31 (m, 2H), 3.17(m, 2H), 3.02 (m, 1H), 2.93-2.82 (m, 2H), 2.77-2.50 (m, 8H), 2.40-2.19(m, 3H), 2.00-1.83 (m, 3H), 1.77-1.43 (m, 5H), 1.41-1.21 (m, 4H), 0.96(t, J=7.5 Hz, 3H), 0.91 (J=7.5 Hz, 3H).

EXAMPLE 22(c)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 4-pentylbenzoylmethyl ester

TLC: Rf0.38 (Hexan:Ethyl Acetate=1:4); NMR: δ 7.81 (d, J=8.4 Hz, 2H),7.36-7.23 (m, 3H), 7.21-7.10 (m, 3H), 5.78 (dd, J=15.0, 5.4 Hz, 1H),5.55 (dd, J=15.0, 8.1 Hz, 1H), 5.33 (s, 2H), 4.47-4.39 (m, 3H), 3.95 (m,1H), 3.41 (s, 3H), 2.97-2.55 (m, 12H), 2.40-2.18 (m, 4H), 2.03-1.84 (m,3H), 1.80-1.58 (m, 3H), 1.40-1.22 (m, 4H), 0.89 (t, J=6.6 Hz, 3H).

EXAMPLE 22(d)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 1,1-dimethylheptyloxycarbonylmethyl ester

TLC: Rf0.42 (Hexane:Ethyl Acetate=1:4); NMR: δ 7.35-7.12 (m, 4H), 5.76(dd, J=15.3, 5.7 Hz, 1H), 5.53 (dd, J=15.3, 8.1 Hz, 1H), 4.51-4.40 (m,5H), 3.95 (m, 1H), 3.42 (s, 3H), 3.00 (bs, 1H), 2.96-2.81 (m, 2H), 2.70(dd, J=18.6, 7.5 Hz, 1H), 2.61-2.48 (m, 6H), 2.40-2.19 (m, 4H),2.00-1.83 (m, 3H), 1.79-1.60 (m, 3H), 1.44 (s, 6H), 1.38-1.20 (m, 8H),0.88 (t, J=6.6 Hz, 3H).

EXAMPLE 22(e)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid dipentylcarbamoylmethyl ester

TLC: Rf0.33 (Hexane:Ethyl Acetate=1:4); NMR: δ 7.36-7.12 (m, 4H), 5.76(dd, J=15.0, 5.4 Hz, 1H), 5.55 (dd, J=15.0, 8.7 Hz, 1H), 4.70 (s, 2H),4.45-4.39 (m, 3H), 3.95 (m, 1H), 3.41 (s, 3H), 3.30 (m, 2H), 3.17 (m,2H), 3.00 (bs, 1H), 2.98-2.80 (m, 2H), 2.77-2.50 (m, 8H), 2.40-2.19 (m,3H), 2.00-1.82 (m, 3H), 1.78-1.50 (m, 5H), 1.40-1.20 (m, 8H), 0.98-0.84(m, 6H).

EXAMPLE 23(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-octyloxyethyl ester

To a solution of(11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid (150 mg; this is the compound described in Example 3 ofWO00/03980), 2-octyloxyethanol (296 mg) and triethylamine (0.12 mL) inethyl acetate (3 mL), 1-mesyloxybenzotriazole (145 mg) was added, andthe mixture was stirred for 4 hours at room temperature. The reactionmixture was added by ethyl acetate, The diluted solution was washed withsaturated aqueous sodium hydrogen carbonate solution, water and brinesuccessively, dried over an anhydrous sodium sulfate, concentrated underreduced pressure and was purified by column chromatography on silica gel(from ethyl acetate:hexane=2:1 to ethyl acetate only) to give the titlecompound (137 mg) having the following physical data.

TLC: Rf0.22 (Ethyl Acetate:Hexane=3:1); NMR: δ 7.35-7.15 (m, 4H), 5.75(dd, J=15.3, 6.0 Hz, 1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.50-4.37 (m,3H), 4.22 (t, J=5.1 Hz, 2H), 4.00-3.90 (m, 1H), 3.62 (t, J=5.1 Hz, 2H),3.46 (t, J=6.9 Hz, 2H), 3.42 (s, 3H), 2.90 (dd, J=13.5, 5.4 Hz, 1H),2.83 (dd, J=13.5, 7.2 Hz, 1H), 2.70 (dd, J=18.6, 7.5 Hz, 1H), 2.65-2.40(m, 6H), 2.40-2.10 (m, 4H), 1.95-1.80 (m, 4H), 1.80-1.50 (m, 3H),1.40-1.20 (m, 10H), 0.90 (t, J=6.9 Hz, 3H).

EXAMPLE 23(a) TO EXAMPLE 23(i)

By the same procedure as describe in Example 23 using correspondingalcohol derivatives instead of 2-octyloxyethanol, the compound of thepresent invention having the following physical data were obtained.

EXAMPLE 23(a)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-(2,2-dimethylpentanoyloxy)ethyl ester

TLC: Rf0.28 (Ethyl Acetate:Hexane=3:1); NMR: δ 7.35-7.10 (m, 4H), 5.77(dd, J=15.3, 5.7 Hz, 1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.40 (m,3H), 4.25 (s, 4H), 4.00-3.90 (m, 1H), 3.41 (s, 3H), 2.96-2.80 (m, 3H),2.67 (dd, J=18.3, 7.5 Hz, 1H), 2.65-2.50 (m, 2H), 2.50 (t, J=7.2 Hz,2H), 2.43 (t, J=2.40-2.10 (m, 4H), 1.95-1.80 (m, 3H), 1.75-1.60 (m, 1H),1.55-1.45 (m, 2H), 1.30-1.20 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 23(b)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 3-butoxypropyl ester

TLC: Rf0.30 (Ethyl Acetate:Hexane=3:1); NMR: δ 7.30-7.10 (m, 4H), 5.77(dd, J=15.3, 5.7 Hz, 1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.40 (m,3H), 4.17 (t, J=7.2 Hz, 2H), 4.00-3.90 (m, 1H), 3.48 (t, J=(t, J=7.2 Hz,1H), 3.42 (s, 3H), 3.40 (t, J=6.6 Hz, 2H), 2.97-2.80 (m, 3H), 2.70 (dd,J=19.2, 7.5 Hz, 1H), 2.65-2.50 (m, 2H), 2.50 (t, J=7.2 Hz, 2H), 2.41 (t,J=7.2 Hz, 2H), 2.36-2.14 (m, 4H), 1.95-1.82 (m, 3H), 1.75-1.60 (m, 1H ),1.60-1.50 (m, 2H), 1.42-1.30 (m, 2H), 0.92 (t, J=7.2 Hz, 3H).

EXAMPLE 23(c)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-butoxyethyl ester

TLC: Rf0.32 (Ethyl Acetate); NMR: δ 7.35-7.11 (m, 4H), 5.75 (dd, J=15.3,5.7 Hz, 1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.39 (m, 3H), 4.21 (m,2H), 3.95 (m, 1H), 3.61 (m, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.42 (s, 3H),3.00 (m, 1H), 2.98-2.80 (m, 2H), 2.78-2.18 (m, 11H), 1.98-1.81 (m, 3H),1.78-1.53 (m, 3H), 1.38 (m, 2H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 23(d)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-pentyloxyethyl ester

TLC: Rf0.36 (Ethyl Acetate); NMR: δ 7.35-7.11 (m, 4H), 5.75 (dd, J=15.3,5.7 Hz, 1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.39 (m, 3H), 4.21 (m,2H), 3.95 (m, 1H), 3.61 (m, 2H), 3.46 (t, J=6.6 Hz, 2H), 3.42 (s, 3H),2.98-2.80 (m, 3H), 2.78-2.18 (m, 11H), 1.98-1.81 (m, 3H), 1.78-1.53 (m,3H), 1.38 (m, 4H), 0.92 (t, J=7.5 Hz, 3H).

EXAMPLE 23(e)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-hexyloxyethyl ester

TLC: Rf0.39 (Ethyl Acetate); NMR: δ 7.36-7.12 (m, 4H), 5.76 (dd, J=15.3,5.7 Hz, 1H), 5.53 (dd, J=15.3, 8.7 Hz, 1H), 4.48-4.40 (m, 3H), 4.21 (m,2H), 3.95 (m, 1H), 3.61 (m, 2H), 3.47-3.40 (m, 5H), 2.98-2.80 (m, 3H),2.78-2.40 (m, 7H), 2.38-2.18 (m, 4H), 1.97-1.82 (m, 3H), 1.70 (m, 1H),1.63-1.52 (m, 2H), 1.40-1.25 (m, 6H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 23(f)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-(2,2-dimethyloctanoyloxy)ethyl ester

TLC: Rf0.20 (Ethyl Acetate: Hexane=3:1); NMR: δ 7.35-7.10 (m, 4H), 5.75(dd, J=15.3, 6.0 Hz, 1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.35 (m,3H), 4.26 (s, 4H), 4.00-3.90 (m, 1H), 3.42 (s, 3H), 3.20-3.10 (br, 1H),2.92 (dd, J=13.5, 5.4 Hz, 1H), 2.83 (dd, J=13.5, 7.2 Hz, 1H), 2.70 (dd,J=18.6, 7.2 Hz, 1H), 2.63-2.50 (m, 2H), 2.50 (t, J=7.5 Hz, 2H), 2.43 (t,J=7.2 Hz, 2H), 2.40-2.15 (m, 4H), 1.95-1.80 (m, 3H), 1.80-1.60 (m, 1H),1.55-1.50 (m, 2H), 1.40-1.15 (m, 8H), 0.90 (t, J=6.9 Hz, 3H).

EXAMPLE 23(g)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-(2,2-diethylpentanoyloxy)ethyl ester

TLC: Rf0.21 (Ethyl Acetate:Hexane=3:1); NMR: δ 7.35-7.10 (m, 4H), 5.76(dd, J=15.3, 6.0 Hz, 1H), 5.53 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.35 (m,3H), 4.27 (s, 4H), 4.00-3.90 (m, 1H), 3.42 (s, 3H), 3.05-3.00 (br, 1H),2.92 (dd, J=13.5, 5.4 Hz, 1H), 2.83 (dd, J=13.5, 7.2 Hz, 1H), 2.70 (dd,J=18.0, 7.2 Hz, 1H), 2.65-2.40 (m, 6H), 2.40-2.10 (m, 4H), 1.95-1.80 (m,3H), 1.80-1.50 (m, 7H), 1.25-1.10 (m, 2H), 0.90 (t, J=7.2 Hz, 3H), 0.78(t, J=7.2 Hz, 6H).

EXAMPLE 23(h)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 4-(4-chlorophenyl)phenyl ester

TLC: Rf0.22 (Hexane:Ethyl Acetate=1:3); NMR: δ 7.52 (d, J=8.7 Hz, 2H),7.47 (d, J=8.6 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 7.24 (m, 1H), 7.20-7.08(m, 5H), 5.72 (dd, J=15.3, 6.6 Hz, 1H), 5.51 (dd, J=15.3, 8.4 Hz, 1H),4.45-4.30 (m, 3H), 3.95 (m, 1H), 3.63 (bs, 1H), 3.40 (s, 3H), 2.90-2.50(m, 9H), 2.39-2.13 (m, 3H), 2.09-1.82 (m, 3H), 1.70 (m, 1H).

EXAMPLE 23(i)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-(adamantan-1-ylcarbonyloxy)ethyl ester

TLC: Rf0.33 (Ethyl Acetate:Hexane:Methanol=30:10:1); NMR: δ 7.32-7.11(m, 4H), 5.75 (dd, J=15.3, 6.0 Hz, 1H), 5.52 (dd, J=15.3, 9.0 Hz, 1H),4.48-4.36 (m, 3H), 4.31-4.22 (m, 4H), 4.02-3.89 (m, 1H), 3.42 (s, 3H),3.20-3.12 (br, 1H), 2.90 (dd, J=13.8, 5.4 Hz, 1H), 2.82 (dd, J=13.8, 7.2Hz, 1H), 2.70 (dd, J=18.3, 7.2 Hz, 1H), 2.65-2.13 (m, 10H), 2.07-1.97(m, 3H), 1.96-1.80 (m, 9H), 1.80-1.60 (m, 7H).

EXAMPLE 23(i)(11α,15α,13E)-9-Oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoicacid 2-(2,2-dipropylpentanoyloxy)ethyl ester

TLC: Rf0.38 (Ethyl Acetate:Hexane:Methanol=30:10:1); NMR: δ 7.32-7.12(m, 4H), 5.75 (dd, J=15.3, 6.0 Hz, 1H), 5.52 (dd, J=15.3, 8.7 Hz, 1H),4.48-4.32 (m, 3H), 4.25 (s, 4H), 4.02-3.88 (m, 1H), 3.42 (s, 3H),3.27-3.20 (br, 1H), 2.90 (dd, J=13.5, 5.4 Hz, 1H), 2.82 (dd, J=13.5, 6.9Hz, 1H), 2.70 (dd, J=18.3, 7.2 Hz, 1H), 2.65-2.12 (m, 10H), 1.94-1.82(m, 3H), 1.75-1.60 (m, 1H), 1.55-1.45 (m, 6H), 1.22-1.09 (m, 6H), 0.89(t, J=7.2 Hz, 9H).

EXAMPLE 24(15α,13E)-9-Oxo-15-hydroxy-16-(4-aminophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

By the same procedure as describe in Reference Example 5, Examples 1, 11and 2 using the compound prepared in Reference Example 11 instead of thecompound prepared in Reference Example 4 and3-(4-t-butoxycarbonylaminophenyl)-2-oxopropylphosphonic acid dimethylester instead of 3-(3-methoxymethylphenyl)-2-oxopropylphosphonic aciddimethyl ester, the compound of the present invention having thefollowing physical data were obtained,

TLC: Rf0.17 (Chloroform:Methanol=9:1); NMR: δ 6.98 (d, J=8.4 Hz, 2H),6.66 (d, J=8.4 Hz, 2H), 5.73 (dd, J=15.9, 6.3 Hz, 1H), 5.47 (dd, J=15.9,8.4 Hz, 1H), 4.38 (m, 1H), 4.10 (m, 1H), 3.61 (m, 1H), 3.10-2.15 (m,15H), 2.00-1.81 (m, 2H), 1.73 (m, 1H).

REFERENCE EXAMPLE 26(2R)-1-(2-Mesyloxyethyl)-2-t-butyldimethylsilyloxymethylpyrrolidin-5-one

Under atmosphere of argon, to a solution of the compound prepared inReference Example 7 (11.9 g) in tetrahydrofuran (50 mL), triethylamine(9.07 mL) was added. Then mesyl chloride (3.68 mL) was dropped into themixture at 0° C., and the mixture was stirred for 30 minutes. Themixture was added by water and was extracted by ethyl acetate. Theextract was washed with 1N hydrochloric acid, saturated aqueous sodiumhydrogen carbonate solution and brine successively, dried over ananhydrous sodium sulfate, concentrated under reduced pressure to givethe title compound having the following physical data, which was usedfor the next reaction without purification.

TLC: Rf0.46 (Ethyl Acetate).

REFERENCE EXAMPLE 27(2R)-1-(2-Iodoethyl)-2-t-butyldimethylsilyloxymethylpyrrolidin-5-one

Under atmosphere of argon, to a solution of the compound prepared inReference Example 26 in acetonitrile (120 mL), sodium iodide (19.5 g)was added, and the mixture was stirred overnight at 80° C. It was cooledto room temperature, the mixture was added by water, and extracted byethyl acetate. The extract was washed with saturated aqueous sodiumhydrogen carbonate solution and brine successively, dried over ananhydrous magnesium sulfate, concentrated under reduced pressure and waspurified by column chromatography on silica gel (ethylacetate:hexane=from 1:3 to 1:1) to give the title compound (11.3 g)having the following physical data.

TLC: Rf0.63 (Hexane:Ethyl Acetate=1:1); NMR: δ 3.92 (m, 1H), 3.81-3.69(m, 2H), 3.62-3.45 (m, 2H), 3.35 (m, 1H), 3.22 (m, 1H), 2.50-2.26 (m,2H), 2.14 (m, 1H), 1.78 (m, 1H), 0.86 (s, 9H), 0.03 (s, 3H), 0.02 (s,3H).

REFERENCE EXAMPLE 285-(2-((2R)-2-t-Butyldimethylsilyloxymethyl-5-oxopyrrolidin-1-yl)ethylthio)thiophene-2-carboxylicacid ethyl ester

Under atmosphere of argon, to a solution thiophene-2-carboxylic acidethyl ester (936 mg) in tetrahydrofuran (50 mL), sulfur powder (240 mg)was added, and the mixture was cooled to −78° C. 2.0M lithiumdiisopropylamide (4.0 mL) was dropped into the mixture, and was stirredfor 35 minutes. Then a solution of the compound prepared in ReferenceExample 27 (1.92 g) in tetrahydrofuran (5 mL) was added, and the mixturewas stirred for 1.5 hour at room temperature. The mixture was pouredinto saturated aqueous ammonium chloride solution, and extracted byt-butyl methyl ether. The extract was washed with saturated aqueoussodium hydrogen carbonate solution, dried over an anhydrous magnesiumsulfate, concentrated under reduced pressure and was purified by columnchromatography on silica gel (ethyl acetate:hexane=from 1:3 to 1:1) togive the title compound (1.86 g) having the following physical data.

TLC: Rf0.54 (Hexane:Ethyl Acetate=1:1); NMR: δ 7.65 (d, J=3.9 Hz, 1H),7.09 (d, J=3.9 Hz, 1H), 4.32 (q, J=7.5 Hz, 2H), 3.86-3.61 (m, 3H), 3.55(m, 1H), 3.32 (m, 1H), 3.22-3.00 (m, 2H), 2.50-2.21 (m, 2H), 2.10 (m,1H), 1.80 (m, 1H), 1.36 (t, J=7.5 Hz, 3H), 0.86 (s, 9H), 0.03 (s, 3H),0.02 (s, 3H).

REFERENCE EXAMPLE 295-(2-((2R)-2-Hydroxymethyl-5-oxopyrrolidin-1-yl)ethylthio)thiophene-2-carboxylicacid ethyl ester

Under atmosphere of argon, to a solution of the compound prepared inReference Example 28 (1.85 g) in tetrahydrofuran (4 mL),tetrabutylammonium fluoride (6.28 mL) was added, and the mixture wasstirred overnight at room temperature. The mixture was added by water,and extracted by ethyl acetate. The extract was washed with brine, driedover an anhydrous sodium sulfate, concentrated under reduced pressure togive the title compound (1.15 g) having the following physical data.

TLC: Rf0.15 (Ethyl Acetate); NMR: δ 7.64 (d, J=3.9 Hz, 1H), 7.10 (d,J=3.9 Hz, 1H), 4.33 (q, J=6.9 Hz, 2H), 3.80-3.68 (m, 3H), 3.60 (m, 1H),3.40 (m, 1H), 3.17 (t, J=7.0 Hz, 2H), 2.58-2.28 (m, 2H), 2.10 (m, 1H),1.98-1.80 (m, 2H), 1.37 (t, J=7.2 Hz, 3H).

EXAMPLE 25(a) TO EXAMPLE 25(c)

By the same procedure as describe in Reference Examples 11, 5, Examples1 and 2 using the compound prepared in Reference Example 29 instead ofthe compound prepared in Reference Example 10 and correspondingphosphonic acid ester derivatives instead of3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl ester, thecompound of the present invention having the following physical datawere obtained.

EXAMPLE 25(a)(15α,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.20 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 7.68 (d,J=3.9 Hz, 1H), 7.15 (dd, J=8.4, 5.4 Hz, 2H), 7.06 (d, J=3.9 Hz, 1H),6.98 (t, J=8.4 Hz, 2H), 5.71 (dd, J=15.0, 5.4 Hz, 1H), 5.48 (dd, J=15.0,9.0 Hz, 1H), 4.37 (m, 1H), 4.11 (m, 1H), 3.82-3.30 (m, 2H), 3.19-2.93(m, 3H), 2.70 (d, J=6.9 Hz, 2H), 2.50-2.18 (m, 3H), 1.71 (m, 1H).

EXAMPLE 25(b)(15α,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.15 (Chloroform:Methanol=9:1); NMR: δ 7.66 (d, J=4.2 Hz, 1H),7.22 (d, J=6.9 Hz, 1H), 7.10-7.00 (m, 3H), 5.69 (dd, J=15.3, 5.4 Hz,1H), 5.48 (dd, J=15.3, 8.7 Hz, 1H), 4.50 (bs, 2H), 4.37 (m, 1H), 4.10(m, 1H), 3.75-3.60 (m, 1H), 3.20-2.93 (m, 3H), 2.80-2.68 (m, 2H),2.50-2.12 (m, 3H), 1.70 (m, 1H).

EXAMPLE 25(c)(15α,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.23 (Chloroform:Methanol:Acetic Acid 9:1:0.1); NMR: δ 7.65 (d,J=3.9 Hz, 1H), 7.50-7.30 (m, 2H), 7.20-7.00 (m, 2H), 5.72 (dd, J=15.3,5.1 Hz, 1H), 5.51 (dd, J=15.3, 8.7 Hz, 1H), 4.82 (bs, 2H), 4.40 (m, 1H),4.12 (m, 1H), 3.65 (m, 1H), 3.23-2.93 (m, 3H), 2.90-2.73 (m, 2H),2.50-2.10 (m, 3H), 1.70 (m, 1H).

REFERENCE EXAMPLE 30 (4R)-4-t-Butoxycarbonylamino-4-formylbutanoic acidethyl ester

Under atmosphere of argon, to a solution of(4R)-5-hydroxy-4-t-butoxycarbonylaminopentanoic acid ethyl ester (15.0g), triethylamine (32.0 mL) and dimethylsulfoxide (39 mL) in ethylacetate (120 mL), a solution of sulfur trioxide pyridine complex (18.3g) in mixed solvent ethyl acetate (30 mL) and dimethylsulfoxide (75 nL)was added at 0° C., and the mixture was stirred for 1 hour. The reactionmixture was added by water (5 mL) at 0° C. and was added by 1Nhydrochloric acid (240 mL). Separated aqueous layer was extracted byethyl acetate. The combined organic layer was washed with water andbrine successively, dried over an anhydrous sodium sulfate, concentratedunder reduced pressure to give the title compound (14.7 g) having thefollowing physical data.

TLC: Rf0.63 (Ethyl Acetate:Hexane=1:1); NMR: δ 9.60 (s, 1H), 5.25-5.15(m, 1H), 4.35-4.20 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 2.50-2.35 (m, 2H),2.35-2.20 (m, 1H), 2.00-1.85 (m, 1H), 1.43 (s, 9H), 1.27 (t, J=7.2 Hz,3H).

REFERENCE EXAMPLE 31(4R,5E)-4-t-Butoxycarbonylamino-7-oxo-8-(4-fluorophenyl)oct-5-enoic acidethyl ester

Under atmosphere of argon, to a solution sodium hydride (2.40 g; 62.6%in oil), in tetrahydrofuran (620 mL), a solution of3-(4-fluorophenyl)-2-oxopropylphosphonic acid dimethyl ester (17.7 g) intetrahydrofuran (100 mL) was added at 0° C., and the mixture was stirredfor 1 hour. The reaction mixture was added by the solution of thecompound prepared in Reference Example 30 (14.7 g) in tetrahydrofuran(80 mL) at 0° C., and the mixture was stirred for 20 minutes. Thereaction mixture was added by t-butyl methyl ether (800 mL) and water(800 mL). The organic layer was washed with water and brinesuccessively, dried over an anhydrous sodium sulfate, concentrated underreduced pressure to give the crude title compound (25.3 g). 1 g of thecrude compound was purified by column chromatography on silica gel(ethyl acetate:hexane=1:3) to give the title compound (636 mg) havingthe following physical data.

TLC: Rf0.74 (Ethyl Acetate:Hexane=1:1); NMR: δ 7.20-7.10 (m, 2H),7.08-6.96(m, 2H), 6.76 (dd, J=15.3, 5.1 Hz, 1H), 6.24 (d, J=15.3 Hz,1H), 4.7-4.6 (m, 1H), 4.4-4.25 (m, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.82 (s,2H), 2.38 (t, J=7.2 Hz, 2H), 2.00-1.75 (m, 2H), 1.42 (s, 9H), 1.25 (t,J=7.2 Hz, 3H).

REFERENCE EXAMPLE 32(4R,5E,7S)-4-t-Butoxycarbonylamino-7-hydroxy-8-(4-fluorophenyl)oct-5-enoicacid ethyl ester

To a solution of the compound prepared in Reference Example 31 (5.56 g)and a solution of (R)-2-methyl-CBS-oxazaborolidine (4.3 mL; 1.0M toluenesolution) in dry tetrahydrofuran (30 mL), borane tetrahydrofuran complex(8.6 mL; 1.0M) was added, and the mixture was stirred for 15 minutes. Tothe mixture, methanol was added, and was diluted by ethyl acetate. Thediluted solution was washed with 1N hydrochloric acid, water and brinesuccessively, dried over an anhydrous magnesium sulfate, concentratedunder reduced pressure to give the title compound having the followingphysical data.

TLC: Rf0.80 (Ethyl Acetate); NMR: δ 7.20-7.09 (m, 2H), 7.02-6.93 (m,2H), 5.67 (dd, J=15.6, 5.7 Hz, 1H), 5.52 (dd, J=15.6, 6.0 Hz, 1H),4.56-4.43 (br, 1H), 4.35-4.27 (m, 1H), 4.20-4.05 (m, 3H), 2.85-2.68 (m,2H), 2.30 (t, J=6.9 Hz, 2H), 1.90-1.70 (m, 2H), 1.43 (s, 9H), 1.26 (t,J=7.2 Hz, 3H).

REFERENCE EXAMPLE 33(4R,5E,7S)-4-Amino-7-hydroxy-8-(4-fluorophenyl)oct-5-enoic acidhydrochloride

To a solution of the compound prepared in Reference Example 32 inethanol (12 mL), 4N hydrogen chloride-dioxane solution (14 mL) was addedat 0° C., and the mixture was stirred for 4 hours. The mixture wasconcentrated under reduced pressure. The obtained crude was disolved inethyl acetate (25 mL) with heat, then cooled to room temperatureovernight. The precipitate was filtrated, washed with cold ethylacetate, dried to give the title compound (2.37 g) having the followingphysical data.

TLC: Rf0.05 (Ethyl Acetate); NMR(CD₃OD): δ 7.28-7.19 (m, 2H), 7.04-6.93(m, 2H), 5.92 (dd, J=15.6, 4.8 Hz, 1H), 5.53 (dd, J=15.6, 8.7 Hz, 1H),4.41-4.32 (m, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.80-3.70 (m, 1H), 2.81 (d,J=5.7 Hz, 2H), 2.28 (t, J=6.9 Hz, 2H), 2.09-1.97 (m, 1H), 1.84-1.75 (m,1H), 1.24 (t, J=7.2 Hz, 3H).

EXAMPLE 26(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid ethyl ester

Under atmosphere of argon, to a solution of 4-(formylmethylthio)butanoicacid ethyl ester (1.82 g) in dry tetrahydrofuran (15 mL), a compoundprepared in Reference Example 33 (2.27 g) was added at room temperature,and the mixture was stirred for 1.5 hours. Then sodiumtriacetoxyborohydride (2.91 g) was added to the mixture, and the mixturewas stirred overnight at room temperature. The reaction mixture wasdiluted by ethyl acetate The diluted solution was washed with water 1Nhydrochloric acid and brine successively, dried over an anhydrous sodiumsulfate, concentrated under reduced pressure and purified by columnchromatography on silica gel (ethyl acetate methanol=30:1) to give thetitle compound (1.80 g) having the following physical data.

TLC: Rf0.33 (Ethyl Acetate). TLC: Rf0.44 (Chloroform:Methanol=9:1); NMR:δ 7.21-7.14 (m, 2H), 7.05-6.96 (m, 2H), 5.75 (dd, J=15.6, 6.0 Hz, 1H),5.50 (dd, J=15.6, 8.4 Hz, 1H), 4.19 (m, 1H), 4.18-4.03 (m, 3H), 3.60 (m,1H), 2.97 (m, 1H), 2.85-2.79 (m, 2H), 2.70-2.18 (m, 9H), 2.01-1.82 (m,3H), 1.79-1.60 (m, 1H), 1.25 (t, J=7.2 Hz, 3H).

EXAMPLE 27(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

By the same procedure as describe in Example 2 using the compoundprepared in Example 26 instead of the compound prepared in Example 1,the compound of the present invention having the following physical datawere obtained.

TLC: Rf0.38 (Chloroform:Methanol:Water=9:1:0.1); NMR: δ 7.20-7.16 (m,2H), 7.04-6.96 (m, 2H), 5.75 (dd, J=15.4, 6.0 Hz, 1H), 5.50 (ddd,J=15.4, 8.5, 1.1 Hz, 1H), 4.39 (m, 1H), 4.11 (m, 1H), 3.62 (m, 1H), 2.95(m, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.67-2.53 (m, 4H), 2.52-2.43 (m, 2H),2.39 (t, J=7.1 Hz, 2H), 2.22 (m, 1H), 1.94-1.83 (m, 2H), 1.68 (m, 1H).

EXAMPLE 27(a) TO EXAMPLE 27(i)

By the same procedure as describe in Reference Examples 31, 32, 33,Examples 26 and 2 using corresponding phosphonic acid ester derivativesinstead of 3-(4-fluorophenyl)-2-oxopropylphosphonic acid dimethyl esterand corresponding carboxylic acid ester derivatives instead of4-(formylmethylthio)butanoic acid ethyl ester, the compound of thepresent invention having the following physical data were obtained.

The compound prepared in Example 27(b) was done by additional procedureof the same as described in Example 5 after the procedure of the same asdescribed in Reference Example 32.

EXAMPLE 27(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.53 (Chloroform:Methanol=9:1); NMR: δ 7.76-7.70 (m, 2H), 7.59(d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.40 (dd, J=8.4, 8.4 Hz, 1H),7.33-7.17 (m, 3H), 7.04 (s, 1H), 5.79 (dd, J=15.3, 5.7 Hz, 1H), 5.51(dd, J=15.3, 8.4 Hz, 1H), 4.55-4.44 (m, 1H), 4.16-4.07 (m, 1H),3.68-3.54 (m, 1H), 3.02-2.90 (m, 3H), 2.70-2.10 (m, 9H), 1.92-1.78 (m,2H), 1.78-1.62 (m, 1H).

EXAMPLE 27(b)(15α)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.19 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.07 (s,1H), 7.21 (t, J=7.2 Hz, 1H), 7.10-6.95 (m, 3H), 3.97-3.80 (m, 2H), 3.72(m, 1H), 3.60-3.25 (m, 3H), 2.84-2.63 (m, 2H), 2.55-2.22 (m, 5H), 2.14(m, 1H), 1.93 (m, 1H), 1.78-1.41 (m, 4H).

EXAMPLE 27(c)(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf0.27 (Chloroform:Methanol=9:1); NMR: δ 8.02 (d, J=8.1 Hz, 2H),7.30-7.15 (m, 3H), 7.10-6.97 (m, 3H), 5.64 (dd, J=15.6, 6.3 Hz, 1H),5.37 (dd, J=15.6, 8.7 Hz, 1H), 4.41-4.32 (m, 1H), 3.83-3.70 (m, 2H),3.09-2.95 (m, 1H), 2.95-2.75 (m, 4H), 2.48-2.25 (m, 5H), 2.20-2.13 (m,1H), 1.72-1.58 (m, 1H).

EXAMPLE 27(d)(15α,13E)-7-(6-Carboxyindol-3-yl)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,2,3,4,5,6,17,18,19,20-decanor-8-azaprost-13-ene

TLC: Rf0.21 (Dichloromethane:Methanol=9:1); NMR(DMSO-d₆): δ 8.08 (d,J=1.2 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.20-7.10(m, 2H), 7.10-6.95 (m, 3H), 5.60 (dd, J=15.3, 6.6 Hz, 1H), 5.43 (dd,J=15.3, 5.4 Hz, 1H), 4.95-4.80 (m, 2H), 4.37 (q, J=6.6 Hz, 1H),3.90-3.75 (m, 2H), 2.91 (dd, J=13.5, 6.6 Hz, 1H), 2.70 (dd, J=13.5, 7.5Hz, 1H), 2.50-2.20 (m, 5H), 2.15-2.00 (m, 1H), 1.75-1.60(m, 1H).

EXAMPLE 27(e)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene

TLC: Rf0.25 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.12 (s,1H), 7.18 (m, 1H), 7.05-6.97 (m, 3H), 5.75 (dd, J=15.3, 5.7 Hz, 1H),5.43 (dd, J=15.3, 5.20 (m, 3H), 4.40 (m, 1H), 4.07 (m, 1H), 3.51 (m,1H), 3.07-2.85 (m, 3H), 2.79 (d, J=6.6 Hz, 2H), 2.50-2.12 (m, 6H),2.04-1.90 (m, 2H), 1.70 (m, 1H).

EXAMPLE 27(f)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxyoxazol-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene

TLC: Rf0.21 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.19 (s,1H), 7.20 (m, 1H), 7.06-6.97 (m, 3H), 5.78 (dd, J=15.3, 6.0 Hz, 1H),5.50 (ddd, J=15.3, 9.0, 1.2 Hz, 1H), 4.40 (m, 2H), 4.07 (m, 1H), 3.47(m, 1H), 2.94 (m, 1H), 2.83-2.75 (m, 4H), 2.50-2.10 (m, 6H), 2.05-1.83(m, 2H), 1.64 (m, 1H).

EXAMPLE 27(g)(15α,13E)-1,7-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,6,17,18,19,20-nonanor-8-azaprost-13-enoicacid

TLC: Rf0.18 (Dichloromethane:Methanol=9:1); NMR: δ 7.70 (d, J=3.9 Hz,1H), 7.21 (t, J=7.8 Hz, 1H), 7.10-6.98 (m, 3H), 6.88 (d, J=3.9 Hz, 1H),5.75 (dd, J=15.0, 6.0 Hz, 1H), 5.46 (dd, J=15.0, 8.7 Hz, 1H), 4.88 (d,J=16.2 Hz, 1H), 4.50-4.40 (m, 1H), 4.10-4.00 (m, 1H), 3.88 (d, J=16.2Hz, 1H), 2.82 (d, J=6.6 Hz, 2H), 2.50-2.15 (m, 6H), 1.80-1.70 (m, 1H).

EXAMPLE 27(h)(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf0.31 (Dichloromethane:Methanol=9:1); NMR: δ 7.98 (d, J=8.1 Hz,2H), 7.78-7.70 (m, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H),7.38 (t, J=7.8 Hz, 1H), 7.34-7.16 (m, 5H), 7.03 (s, 1H), 5.65 (dd,J=15.0, 6.0 Hz, 1H), 5.37 (dd, J=15.0, 7.8 Hz, 1H), 4.50-4.40 (m, 1H),3.80-3.65 (m, 2H), 3.05-2.60 (m, 5H), 2.40-2.20 (m, 2H), 2.20-2.00 (m,1H), 1.70-1.55 (m, 1H).

EXAMPLE 27(i)(15α,13E)-1,5-(2,5-Interthienylene)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoicacid

TLC: Rf0.59 (Dichloromethane:Methanol:Acetic Acid=90:10:1); NMR: δ7.74-7.68 (m, 2H), 7.61 (d, J=3.9 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.50(d, J=8.4 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.32-7.14 (m, 3H), 7.02 (s,1H), 6.73 (d, J=3.9 Hz, 1H), 5.75 (dd, J=15.3, 6.3 Hz, 1H), 5.47 (dd,J=15.3, 8.4 Hz, 1H), 4.50-4.40 (m, 1H), 4.05-3.95 (m, 1H), 3.65-3.40 (m,1H), 2.90 (d, J=6.9 Hz, 2H), 2.85-2.70 (m, 3H), 2.50-2.10 (m, 3H),1.85-1.65 (m, 3H).

REFERENCE EXAMPLE 34(2R)-1-(2-(3-Cyclopentylpropanoyloxy)ethyl)-2-t-butyldimethylsilyloxymethylpyrrolidin-5-one

Under atmosphere of argon, to a solution of the compound prepared inReference Example 7 (3.78 g) and triethylamine (2.9 mL) in methylenechloride (30 mL), 3-cyclopentylpropanoyl chloride (2.67 g) was added at0° C., and the mixture was stirred for 2 hours. The mixture was pouredinto water and was extracted by diethyl ether. The extract was washedwith brine, dried over an anhydrous sodium sulfate, concentrated underreduced pressure to give the title compound having the followingphysical data, which was used for the next reaction withoutpurification.

TLC: Rf0.40 (Ethyl Acetate:Hexane=1:1).

REFERENCE EXAMPLE 35(2R)-1-(2-(3-Cyclopentylpropanoyloxy)ethyl)-2-hydroxymethylpyrrolidin-5-one

Under atmosphere of argon, to a solution of the compound prepared inReference Example 34 in tetrahydrofuran (20 mL), tetrabutylammoniumfluoride (16.6 mL; 1.0 M tetrahydrofuran solution) was added at roomtemperature, and the mixture was stirred for 2 hours. The mixture waspoured into saturated aqueous ammounium chloride solution, and extractedby ethyl acetate. The extract was washed with saturated aqueousammounium chloride solution and brine successively, dried over ananhydrous sodium sulfate, concentrated under reduced pressure andpurified by column chromatography on silica gel (from ethylacetate:hexane=2:1 to ethyl acetate:methanol=40:1) to give the titlecompound (2.40 g) having the following physical data.

TLC: Rf0.35 (Ethyl Acetate:Methanol=20:1).

REFERENCE EXAMPLE 36(2R)-1-(2-(3-Cyclopentylpropanoyloxy)ethyl)-2-formylpyrrolidin-5-one

Under atmosphere of argon, to a solution of the compound prepared inReference Example 35 (2.40 g) and diisopropylethylamine (8.7 mL) inmixed solvent of ethyl acetate (15 mL) and dimethylsulfoxide (15 mL),sulfur trioxide pyridine complex (3.98 g) was added, and the mixture wasstirred for 30 minutes. The reaction mixture was added by small amountof water, and was poured into 1N hydrochloric acid, and was extracted byethyl acetate. The extract was washed with water and brine successively,dried over an anhydrous magnesium sulfate, concentrated under reducedpressure to give the title compound having the following physical data,which was used for the next reaction without purification.

TLC: Rf0.57 (Ethyl Acetate:Methanol=20:1).

REFERENCE EXAMPLE 37(13E)-9,15-Dioxo-16-(4-fluorophenyl)-6-(3-cyclopentylpropanoyloxy)-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene

Under atmosphere of argon, to a solution of3-(4-fluorophenyl)-2-oxopropylphosphonic acid dimethyl ester (2.31 g) indry tetrahydrofuran (90 mL), sodium hydride (341 mg; 62.6% in oil) wasadded at room temperature, and the mixture was stirred for 30 minutes.Then the compound prepared in Reference Example 36 was added to themixture and the mixture was stirred for 1 hour. The reaction mixture wasdiluted by t-butyl methyl ether. The diluted solution was washed withwater and brine successively, dried over an anhydrous magnesium sulfate,concentrated under reduced pressure to give the title compound havingthe following physical data, which was used for the next reactionwithout purification.

TLC: Rf0.75 (Ethyl Acetate:Methanol=20:1).

REFERENCE EXAMPLE 38(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-6-(3-cyclopentylpropanoyloxy)-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene

Under atmosphere of argon, a solution of the compound prepared inReference Example 37 and (R)-2-methyl-CBS-oxazaborolidine (2.7 mL; 1.0 Mtoluene solution) in dry tetrahydrofuran (10 mL) was added by boranetetrahydrofuran complex (5.4 mL; 1.0M tetrahydrofuran solution) at 0°C., and the mixture was stirred for 20 minutes. The mixture was added bymethanol, and diluted by ethyl acetate. The organic layer was washedwith 1N hydrochloric acid, water and brine successively, dried over ananhydrous sodium sulfate, concentrated under reduced pressure and waspurified by column chromatography on silica gel (from ethylacetate:hexane:methanol=30:10:1 to ethyl acetate:methanol=30:1) to givethe title compound (2.58 g) having the following physical data.

TLC: Rf0.50 (Ethyl Acetate:Methanol=20:1).

REFERENCE EXAMPLE 39(15α,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-(3-cyclopentylpropanoyloxy)-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene

Under atmosphere of argon, a solution of the compound prepared inReference Example 38 (2.08 g) and imidazole (0.61 g) indimethylformamide (15 mL) was added by t-butyldimethylsilyl chloride(1.13 g) at room temperature. After the mixture was stirred overnight,the reaction mixture was diluted by t-butyl methyl ether. The extractwas washed with water and brine successively, dried over an anhydroussodium sulfate, concentrated under reduced pressure was purified bycolumn chromatography on silica gel (ethyl acetate:hexane=from 1:2 to1:1) to give the title compound (1.56 g) having the following physicaldata.

TLC: Rf0.81 (Ethyl Acetate).

REFERENCE EXAMPLE 40(15α,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-hydroxy-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene

To a solution of the compound prepared in Reference Example 39 (1.56 g)in mixed solvent of methanol (5 mL) and 1,2-dimethoxyethane (5 mL), 2Naqueous sodium hydroxide solution (3 mL) was added at room temperature,and the mixture was stirred for 1 hour. The reaction mixture was dilutedby t-butyl methyl ether and tetrahydrofuran. The diluted solution waswashed with water and brine successively, dried over an anhydrous sodiumsulfate, concentrated under reduced pressure to give the title compoundhaving the following physical data, which was used for the next reactionwithout purification.

TLC: Rf0.15 (Ethyl Acetate).

REFERENCE EXAMPLE 41(15α,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-mesyloxy-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene

Under atmosphere of argon, to a solution of the compound prepared inReference Example 40 (600 mg) and triethylamine (0.31 mL) intetrahydrofuran (6 mL), mesyl chloride (0.14 mL) was added at 0° C., andthe mixture was stirred for 1 hour. The reaction mixture was diluted byt-butyl methyl ether. The diluted solution was washed with 1Nhydrochloric acid, water and brine successively, dried over an anhydroussodium sulfate, concentrated under reduced pressure to give the titlecompound having the following physical data, which was used for the nextreaction without purification

TLC: Rf0.60 (Ethyl Acetate).

REFERENCE EXAMPLE 42(15α,13E)-9-Oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-6-iodo-1,2,3,4,5,17,18,19,20-nonanor-8-azaprost-13-ene

A suspension of the compound prepared in Reference Example 41 and sodiumiodide (450 mg) in acetonitrile (15 mL) was refluxed for 12 hours. Itwas cooled to room temperature, the mixture was poured into water, andextracted by t-butyl methyl ether. The extract was washed with saturatedaqueous sodium thiosulfate solution and brine successively, dried overan anhydrous sodium sulfate, concentrated under reduced pressure and waspurified by column chromatography on silica gel (ethylacetate:hexane=1:2) to give the title compound (630 mg) having thefollowing physical data.

TLC: Rf0.92 (Ethyl Acetate).

REFERENCE EXAMPLE 43(15α,13E)-3,3-Ethano-9-oxo-15-t-butyldimethylsilyloxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid methyl ester

Under atmosphere of argon, to a solution of the compound prepared inReference Example 42 (90 mg) and2-(1-(acetylthiomethyl)cyclopropyl)acetic acid methyl ester (42 mg) indry methanol (2 mL), potassium carbonate (58 mg) was added at roomtemperature, and the mixture was stirred for 6 hours. The reactionmixture was diluted by t-butyl methyl ether. The diluted solution waswashed with saturated aqueous ammounium chloride solution and brinesuccessively, dried over an anhydrous sodium sulfate, concentrated underreduced pressure and was purified by column chromatography on silica gel(ethyl acetate:hexane=from 1:3 to 1:1) to give the title compound (90mg) having the following physical data.

TLC: Rf0.42 (Ethyl Acetate:Hexane=1:1).

EXAMPLE 28(15α,13E)-3,3-Ethano-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

By the same procedure as describe in Examples 7 and 2 using the compoundprepared in Reference Example 43 instead of the compound prepared inReference Example 14, the compound of the present invention having thefollowing physical data were obtained.

TLC: Rf0.50 (Chloroform:Methanol=9:1); NMR: δ 7.22-7.13 (m, 2H),7.08-6.96 (m, 2H), 5.76 (dd, J=15.3, 5.7 Hz, 1H), 5.51 (dd, J=15.3, 8.7Hz, 1H), 4.48-4.38 (m, 1H), 4.16-4.05 (m, 1H), 3.67-3.53 (m, 1H),3.10-2.95 (m, 1H), 2.88-2.79 (m, 2H), 2.76 (d, J=13.5 Hz, 1H), 2.68-2.50(m, 4H), 2.43-2.16 (m, 5H), 1.75-1.63 (m, 1H), 0.65-0.50 (m, 4H).

EXAMPLE 28(a) TO EXAMPLE 28(b)

By the same procedure as describe in Reference Example 43, Examples 7and 2 using corresponding derivatives instead of2-(1-(acetylthiomethyl)cyclopropyl)acetic acid methyl ester, thecompound of the present invention having the following physical datawere obtained.

EXAMPLE 28(a)(15α,13E)-1,5-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.45 (Chloroform:Methanol=9:1); NMR: δ 8.00 (d, J=8.4 Hz, 2H),7.38 (d, J=8.4 Hz, 2H), 7.20-7.10 (m, 2H), 7.07-6.96 (m, 2H), 5.65 (dd,J=15.3, 5.4 Hz, 1H), 5.47 (dd, J=15.3, 9.3 Hz, 1H), 4.35 (m, 1H), 4.10(m, 1H), 3.67 (m, 1H), 3.30-3.00 (m, 3H), 2.75 (d, J=6.9 Hz, 2H),2.48-2.08 (m, 3H), 1.70 (m, 1H).

EXAMPLE 28(b)(15α,13E)-1,5-(1,3-Interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.45 (Chloroform:Methanol=9:1); NMR: δ 8.05 (m, 1H), 7.88 (d,J=7.8 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.18-7.02(m, 2H), 7.01-6.93 (m, 2H), 5.68 (dd, J=15.6, 5.7 Hz, 1H), 5.45 (dd,J=15.6, 8.7 Hz, 1H), 4.60 (bs, 2H), 4.33 (m, 1H), 4.10 (m, 1H), 3.64 (m,1H), 3.22-2.98 (m, 3H), 2.75 (d, J=6.6 Hz, 2H), 2.50-2.08 (m, 3H), 1.68(m, 1H).

EXAMPLE 29(a) TO EXAMPLE 29(m)

By the same procedure as describe in Reference Example 5, Examples 1 and2 using the compound prepared in Reference Example 11 or correspondingcarboxylic acid ester derivatives instead of the compound prepared inReference Example 4 and corresponding phosphonic acid ester derivativesinstead of 3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethylester, the compound of the present invention having the followingphysical data were obtained.

EXAMPLE 29(a)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(4-fluoromethylbenzyloxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.44 (Chloroform:Methanol=9:1); NMR: δ 7.65 (d, J=8.1 Hz, 2H),7.55 (d, J=8.1 Hz, 2H), 7.28-7.20 (m, 1H), 6.88-6.78 (m, 3H), 5.75 (dd,J=15.3, 5.7 Hz, 1H), 5.48 (dd, J=15.3, 8.1 Hz, 1H), 5.12 (s, 2H), 4.41(q, J=6.3 Hz, 1H), 4.3-3.4 (br), 4.17-4.07 (m, 1H), 3.68-3.57 (m, 1H),3.01-2.88 (m, 1H), 2.82 (d, J=6.3 Hz, 2H), 2.70-2.10 (m, 9H), 1.96-1.82(m, 2H), 1.78-1.62 (m, 1H).

EXAMPLE 29(b)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-3-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.47 (Chloroform:Methanol=9:1); NMR: δ 8.72 (s, 1H), 8.45 (d,J=3.3 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.39 (dd, J=7.8, 3.3 Hz, 1H),7.16 (dd, J=8.1, 8.1 Hz, 1H), 7.04 (s, 1H), 6.80-6.75 (m, 2H), 5.85 (dd,J=15.3, 4.8 Hz, 1H), 5.62 (dd, J=15.3, 8.7 Hz, 1H), 5.24 (d, J=13.2 Hz,1H), 5.17 (d, J=13.2 Hz, 1H), 4.35-4.30 (m, 1H), 4.20-4.10 (m, 1H),3.53-3.40 (m, 1H), 3.30-3.16 (m, 1H), 2.8-2.3 (m, 10H), 2.3-2.1 (m, 1H),1.95-1.8 (m, 2H), 1.8-1.6 (m, 1H).

EXAMPLE 29(c)(15α,13E)-9-Oxo-15-hydroxy-16-cyclopropyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.39 (Chloroform:Methanol=9:1); NMR: δ 5.80 (dd, J=15.6, 6.0 Hz,1H), 5.58 (ddd, J=15.6, 8.4, 1.0 Hz, 1H), 4.30 (m, 1H), 4.15 (m, 1H),3.77-3.05 (m, 4H), 2.77-2.08 (m, 9H), 2.00-1.70 (m, 3H), 1.53-1.41 (m,2H), 0.72 (m, 1H), 0.60-0.42 (m, 2H), 0.20-0.02 (m, 2H).

EXAMPLE 29(d)(15α,13E)-9-Oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.24 (Chloroform:Methanol=9:1); NMR: δ 8.09 (s, 1H), 7.38-7.14(m, 5H), 5.80 (dd, J=15.3, 6.0 Hz, 1H), 5.47 (dd, J=15.3, 8.7 Hz, 1H),4.40 (m, 1H), 4.21-3.61 (m, 4H), 3.38-3.16 (m, 3H), 2.97-2.79 (m, 2H),2.52-2.18 (m, 3H), 1.76 (m, 1H).

EXAMPLE 29(e)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.27 (Chloroform:Methanol=9:1); NMR: δ 8.08 (s, 1H), 7.20 (m,1H), 7.08-6.95 (m, 3H), 5.80 (dd, J=15.3, 5.7 Hz, 1H), 5.50 (dd, J=15.3,8.7 Hz, 1H), 4.40 (m, 1H), 4.12 (m, 1H), 3.70 (m, 1H), 3.50-2.95 (m,5H), 2.85-2.78 (m, 2H), 2.50-2.19 (m, 6H), 1.77 (m, 1H).

EXAMPLE 29(f)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-2-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.30 (Chloroform:Methanol=9:1); NMR: δ 8.57 (d, J=5.4 Hz, 1H),7.80 (dt, J=1.5, 7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.32 (m, 1H), 7.22(t, J=7.8 Hz, 1H), 6.99-6.85 (m, 2H), 6.80 (d, J=7.8 Hz, 1H), 5.85 (dd,J=15.0, 4.8 Hz, 1H), 5.59 (ddd, J=15.0, 8.7, 1.2 Hz, 1H), 5.32 (s, 2H),4.43 (m, 1H), 4.11 (m, 1H), 3.43 (m, 1H), 3.18 (m, 1H), 2.88-2.18 (m,13H), 1.97-1.83 (m, 2H), 1.72 (m, 1H).

EXAMPLE 29(g)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-4-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.30 (Chloroform:Methanol=9:1); NMR: δ 8.58 (d, J=6.0 Hz, 2H),7.39 (d, J=6.0 Hz, 2H), 7.22 (t, J=7.8 Hz, 1H), 6.88-6.70 (m, 3H), 5.72(dd, J=15.3, 5.7 Hz, 1H), 5.45 (dd, J=15.3, 8.1 Hz, 1H), 5.12 (s, 2H),4.32 (m, 1H), 4.11 (m, 1H), 3.59 (m, 1H), 3.30 (m, 1H), 2.99 (m, 1H),2.78 (m, 2H), 2.69-2.12 (m, 10H), 1.98-1.80 (m, 2H), 1.63 (m, 1H).

EXAMPLE 29(h)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(pyridin-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.37 (Chloroform:Methanol=9:1); NMR: δ 8.74 (m, 1H), 7.93 (s,1H), 7.84 (dt, J=1.8, 7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.65 (d,J=8.1 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.37-7.23 (m, 2H), 5.88 (dd,J=15.0, 4.5 Hz, 1H), 5.64 (ddd, J=15.0, 9.0, 1.5 Hz, 1H), 5.45 (bs, 2H),4.58 (m, 1H), 4.10 (m, 1H), 3.40 (m, 1H), 3.21 (m, 1H), 3.02-2.80 (m,2H), 2.78-2.10 (m, 9H), 1.99-1.82 (m, 2H), 1.73 (m, 1H).

EXAMPLE 29(i)(15α,13E)-9-Oxo-15-hydroxy-16-cyclopentyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.22 (Chloroform:Methanol=9:2); NMR: δ 8.10 (s, 1H), 5.79 (dd,J=15.6, 6.0 Hz, 1H), 5.55 (d, J=15.6, 8.7 Hz, 1H), 4.40-3.63 (m, 5H),3.58-3.24 (m, 3H), 2.57-2.08 (m, 3H), 1.98-1.40 (m, 10H), 1.10 (m, 2H).

EXAMPLE 29(j)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.19 (Chloroform:Methanol=9:2); NMR: δ 8.08 (s, 1H), 7.37-7.10(m, 4H), 5.80 (dd, J=15.3, 5.7 Hz, 1H), 5.52 (dd, J=15.3, 8.4 Hz, 1H),4.80-4.50 (m, 3H), 4.41 (m, 1H), 4.11 (m, 1H), 3.94-3.62 (m, 4H),3.39-3.19 (m, 3H), 2.88-2.79 (m, 2H), 2.50-2.17 (m, 3H), 1.72 (m, 1H).

EXAMPLE 29(k)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.24 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.05 (s,1H), 7.80-7.65 (m, 2H), 7.58 (d, J=7.5 Hz, 1H), 7.51 (d, J=7.5 Hz, 1H),7.39 (t, J=7.8 Hz, 1H), 7.35-7.15 (m, 3H), 7.03 (s, 1H), 5.82 (dd,J=15.0, 5.7 Hz, 1H), 5.52 (d, J=15.0, 8.7 Hz, 1H), 4.50 (m, 1H),4.19-4.02 (m, 1H), 3.70 (m, 1H), 3.36-3.08 (m, 3H), 3.00-2.82 (m, 2H),2.50-2.10 (m, 3H), 1.72 (m, 1H).

EXAMPLE 29(l)(15α,13E)-9-Oxo-15-hydroxy-16-(5-methylfuran-2-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.26 (Dichloromethane:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.09(s, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.90-5.84 (m, 1H), 5.79 (dd, J=15.3,6.0 Hz, 1H), 5.55 (ddd, J=15.3, 6.0, 1.2 Hz, 1H), 4.45 (q, J=6.3 Hz,1H), 4.12 (q, J=7.5 Hz, 1 H), 3.84-3.72 (m, 1H), 3.46-3.18 (m, 3H), 2.82(d, J=6.3 Hz, 2H), 2.50-2.20 (m, 3H), 2.24 (s, 3H), 1.80-1.70 (m, 1H).

EXAMPLE 29(m)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-5-(6-carboxypyridin-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.21 (Chloroform:Methanol=4:1); NMR: δ 7.97 (m, 1H), 7.69 (m,1H), 7.38 (m, 1H), 7.21-7.15 (m, 2H), 7.06-6.97 (m, 2H), 5.75 (dd,J=15.0, 5.7 Hz, 1H), 5.51 (ddd, J=15.0, 8.4, 1.0 Hz, 1H), 4.40 (m, 1H),4.10 (m, 1H), 3.58 (m, 1H), 3.38-3.15 (m, 3H), 2.83 (d, J=6.6 Hz, 2H),2.57-2.20 (m, 3H), 1.77 (m, 1H).

EXAMPLE 30(a) TO EXAMPLE 30(e)

By the same procedure as describe in Example 16 using the compoundprepared in Example 3(l) or Example 29(e) and corresponding alcoholderivatives instead of 2-pentanoyloxyethanol, the compound of thepresent invention having the following physical data were obtained.

EXAMPLE 30(a)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid dibutylcarbamoylmethyl ester

TLC: Rf0.73 (Chloroform:Methanol=9:1); NMR: δ 7.17 (m, 2H), 6.99 (m,2H), 5.75 (dd, J=15.6, 5.1 Hz, 1H), 5.52 (dd, J=15.6, 8.4 Hz, 1H), 4.69(s, 2H), 4.40 (m, 1H), 4.11 (m, 1H), 3.58 (m, 1H), 3.28 (m, 2H),3.20-3.00 (m, 3H), 2.81 (d, J=6.6 Hz, 2H), 2.70-2.47 (m, 7H), 2.40-2.18(m, 3H), 1.95 (m, 2H), 1.88-1.42 (m, 5H), 1.41-1.22 (m, 4H), 1.00-0.83(m, 6H).

EXAMPLE 30(b)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-(2,2-diethylpentanoyloxy)ethyl ester

TLC: Rf0.29 (Ethyl Acetate); NMR: δ 7.22-7.13 (m, 2H), 7.07-6.97 (m,2H), 5.75 (dd, J=15.3, 6.0 Hz, 1H), 5.50 (dd, J=15.3, 8.7 Hz, 1H),4.43-4.32 (m, 1H), 4.25 (s, 4H), 4.18-4.06 (m, 1H), 3.79-3.56 (m, 1H),3.02-2.88 (m, 1H), 2.86-2.79 (m, 2H), 2.70-2.48 (m, 4H), 2.48-2.31 (m,4H), 2.31-2.17 (m, 1H), 1.97-1.82 (m, 3H), 1.78-1.60 (m, 1H), 1.60-1.48(m, 6H), 1.22-1.10 (m, 2H), 0.89 (t, J=7.2 Hz, 3H), 0.77 (t, J=7.5 Hz,6H).

EXAMPLE 30(c)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-(adamantan-1-ylcarbonyloxy)ethyl ester

TLC: Rf0.64 (Dichloromethane:Methanol=9:1); NMR: δ 7.20-7.10 (m, 2H),7.05-6.95 (m, 2H), 5.74 (dd, J=14.7, 6.0 Hz, 1H), 5.50 (ddd, J=14.7,8.4, 1.5 Hz, 11), 4.45-4.35 (m, 1H), 4.30-4.20 (m, 4H), 4.15-4.05 (m,1H), 3.70-3.55 (m, 1H), 3.00-2.90 (m, 1H), 2.81 (d, J=6.0 Hz, 2H),2.70-2.35 (m, 8H), 2.30-2.15 (m, 1H), 2.05-1.95 (m, 3H), 1.95-1.80 (m,9H), 1.80-1.60 (m, 6H).

EXAMPLE 30(d)(15α,13E)-9-Oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid 2-(1-ethyl-1-methylbutanoyloxy)ethyl ester

TLC: Rf0.34 (Ethyl Acetate); NMR: δ 7.20-7.10 (m, 2H), 7.05-6.95 (m,2H), 5.23 (dd, J=15.6, 6.0 Hz, 1H), 5.50 (ddd, J=15.6, 8.4, 1.5 Hz, 1H),4.40-4.30 (m, 1H), 4.27 (s, 4H), 4.15-4.05 (m, 1H), 3.70-3.50 (m, 1H),3.00-2.90 (m, 1H), 2.81 (d, J=6.6 Hz, 2H), 2.70-2.15 (m, 8H), 1.95-1.85(m, 3H), 1.75-1.60 (m, 3H), 1.50-1.40 (m, 2H), 1.09 (s, 3H), 0.82 (t,J=7.5 Hz, 6H).

EXAMPLE 30(e)(15α,13E)-9-Oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-(2-(1-ethyl-1-methylbutanoyloxy)ethoxycarbonyl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene

TLC: Rf0.30 (Ethyl Acetate); NMR: δ 7.99 (s, 1H), 7.17 (t, J=7.5 Hz,1H), 7.05-7.00 (m, 1H), 7.00-6.90 (m, 2H), 5.80 (dd, J=15.3, 6.0 Hz,1H), 5.50 (ddd, J=16.2, 8.7, 1.5 Hz, 1H), 4.56-4.45 (m, 2H), 4.40-4.30(m, 3H), 4.25-4.15 (m, 1H), 3.75-3.65 (m, 1H), 3.40 (t, J=6.6 Hz, 2H),3.30-3.15 (m, 1H), 2.80-2.75 (m, 2H), 2.40-2.15 (m, 6H), 2.08 (d, J=4.5Hz, 1H), 1.80-1.60 (m, 3H), 1.50-1.40 (m, 2H), 1.09 (s, 3H), 0.80 (t,J=7.5 Hz, 6H).

EXAMPLE 31(15α,13E)-9-Oxo-15-hydroxy-16-(3,4-dihydroxyphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

By the same procedure as describe in Reference Example 5, Examples 1, 7and 2 using9-oxo-12-formyl-13,14,15,16,17,18,19,20-octanoyl-5-thia-8-azaprostanoicacid butyl ester instead of the compound prepared in Reference Example 4and 3-(3,4-bis(t-butyldimethylsilyloxy)phenyl)-2-oxopropylphosphonicacid dimethyl ester instead of3-(3-methoxymethylphenyl)-2-oxopropylphosphonic acid dimethyl ester, thecompound of the present invention having the following physical datawere obtained.

TLC: Rf0.14 (Dichloromethane:Methanol:Acetic Acid=90:10:1); NMR(CD₃OD):δ 6.67 (d, J=7.8 Hz, 1H), 6.61 (d, J=1.8 Hz, 1H), 6.49 (dd, J=7.8, 1.8Hz, 1H), 5.68 (dd, J=15.3, 7.2 Hz, 1H), 5.33 (dd, J=15.3, 9.0 Hz, 1H),4.30-4.20 (m, 1H), 4.20-4.10 (m, 1H), 3.55-3.45 (m, 1H), 2.90-2.70 (m,2H), 2.70-2.15 (m, 10H), 1.95-1.80 (m, 2H), 1.80-1.60 (m, 1H).

EXAMPLE 32(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(2-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

By the same procedure as describe in Reference Examples 31, 32, 33,Examples 26 and 2 using3-(3-(2-methylphenyl)phenyl)-2-oxopropylphosphonic acid dimethyl esterinstead of 3-(4-fluorophenyl)-2-oxopropylphosphonic acid dimethyl esterand 4-(formylmethyl)benzoic acid ethyl ester instead of4-(formylmethylthio)butanoic acid ethyl ester, the compound of thepresent invention having the following physical data were obtained.

TLC: Rf0.41 (Dichloromethane:Methanol=9:1); NMR: δ 7.99 (d, J=8.4 Hz,2H), 7.40-7.14 (m, 10H), 5.65 (dd, J=15.3, 6.0 Hz, 1H), 5.39 (dd,J=15.3, 8.7 Hz, 1H), 4.45-4.35 (m, 1H), 3.85-3.70 (m, 2H), 3.05-2.70 (m,5H), 2.40-2.20 (m, 5H), 2.20-2.00 (m, 1H), 1.70-1.55 (m, 1H).

EXAMPLE 32(a) TO EXAMPLE 32(s)

By the same procedure as describe in Reference Examples 31, 32, 33,Examples 26 and 2 using corresponding phosphonic acid ester instead of3-(3-(2-methylphenyl)phenyl)-2-oxopropylphosphonic acid dimethyl esterand corresponding carboxylic acid ester derivatives instead of4-(formylmethyl)benzoic acid ethyl ester, the compound of the presentinvention having the following physical data were obtained.

EXAMPLE 32(a)(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(3-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf0.32 (Dichloromethane:Methanol=9:1); NMR: δ 7.98 (d, J=8.4 Hz,2H), 7.50-7.30 (m, 6H), 7.24-7.14 (m, 4H), 5.64 (dd, J=15.3, 6.0 Hz,1H), 5.36 (dd, J=15.3, 8.4 Hz, 1H), 4.50-4.40 (m, 1H), 3.80-3.65 (m,2H), 3.00-2.70 (m, 5H), 2.45-2.20 (m, 5H), 2.20-2.00 (m, 1H), 1.70-1.55(m, 1H).

EXAMPLE 32(b)(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf0.32 (Dichloromethane:Methanol:Water=9:1); NMR: δ 7.98 (d, J=8.4Hz, 2H), 7.50-7.44 (m, 3H), 7.44-7.32 (m, 2H), 7.28-7.14 (m, 5H), 5.64(dd, J=15.6, 6.0 Hz, 1H), 5.36 (dd, J=15.6, 8.7 Hz, 1H), 4.45-4.35 (m,1H), 3.80-3.65 (m, 2H), 3.00-2.70 (m, 5H), 2.40-2.20 (m, 5H), 2.20-2.00(m, 1H), 1.70-1.55 (m, 1H).

EXAMPLE 32(c)(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(4-trifluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf0.51 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.00 (d,J=8.1 Hz, 2H), 7.69 (m, 4H), 7.55-7.13 (m, 6H), 5.65 (dd, J=15.0, 6.0Hz), 1H), 5.39 (dd, J=15.0, 8.4 Hz, 1H), 4.41 (m, 1H), 3.81-3.69 (m,2H), 3.10-2.70 (m, 5H), 2.43-1.30 (m, 5H).

EXAMPLE 32(d)(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(3,5-ditrifluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf0.53 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.01-7.98(m, 4H), 7.86 (s, 1H), 7.58-7.40 (m, 3H), 7.37-7.20 (m, 3H), 5.68 (dd,J=15.6, 6.0 Hz, 1H), 5.44 (dd, J=15.6, 8.4 Hz, 1H), 4.43 (m, 1H),3.83-3.78 (m, 2H), 3.18-2.80 (m, 6H), 2.42-2.22 (m, 2H), 2.14 (m, 1H),1.65 (m, 1H).

EXAMPLE 32(e)(15α,13E)-1,6-(1,4-Interphenylene)-9-oxo-15-hydroxy-16-(3-(4-t-butylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoicacid

TLC: Rf0.51 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 7.98 (d,J=8.4 Hz, 2H), 7.59-7.33 (m, 7H), 7.25-7.16 (m, 3H), 5.63 (dd, J=15.3,5.7 Hz, 1H), 5.39 (dd, J=15.3, 9.0 Hz, 1H), 4.21 (m,1H), 3.80-3.65 (m,2H), 3.00-2.68 (m, 6H), 2.40-1.40 (m, 4H), 1.35 (s, 9H).

EXAMPLE 32(f)(15α)-9-Oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.32 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 1.72 (m, 1H) 2.30 (m, 3 H) 3.06 (m, 7 H) 3.68 (m, 1 H) 4.11 (m, 14H) 4.47 (m, 1 H)5.51 (dd, J=15.38, 8.79 Hz, 1 H) 5.82 (dd, J=15.38, 5.77 Hz, 1 H) 7.35(m, 9 H) 8.07 (s, 1 H).

EXAMPLE 32(g)(15α)-9-Oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.33 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ1.71 (m, 1H) 2.38 (m, 8 H) 2.92 (m, 2 H) 3.23 (m, 3 H) 3.69 (m, 1H) 4.10(m, 1 H)4.47 (m, 1 H) 5.51 (dd, J=15.38, 8.52 Hz, 1 H) 5.82 (dd, J=15.38, 5.77Hz, 1 H) 7.31 (m, 8 H) 8.01 (s, 1 H).

EXAMPLE 32(h)(15α)-9-Oxo-15-hydroxy-16-(3-(4-chlorophenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.28 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 1.69 (m,1H) 2.30 (m, 3 H) 2.90 (m, 2 H) 3.44 (m, 6 H) 4.11 (m, 1 H) 4.46(m, 1H)5.52 (dd, J=15.38, 8.79 Hz, 1 H) 5.83 (dd, J=15.38, 5.77 Hz, 1 H) 7.35(m, 8 H) 8.07 (s, 1 H).

EXAMPLE 32(i)(15a)-9-Oxo-15-hydroxy-16-(3-(4-methoxyphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.32 (Chloroform:Methanol:Acetic Acid=9:1:0.1); NMR: δ 1.70 (m, 1H) 2.53 (m, 7 H) 3.21 (m, 3 H) 3.69 (m, 1 H) 3.85 (s, 3 H) 4.09 (m, 1 H)4.46 (m, 1 H) 5.51 (dd, J=15.38, 8.79 Hz, 1 H) 5.82 (dd, J=15.38, 6.04Hz, 1 H) 7.22 (m, 8 H) 8.07 (s, 1 H).

EXAMPLE 32(I)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.46 (Chloroform:Methanol=9:1); NMR: δ 8.03 (s, 1H), 7.94-7.82(m, 3H), 7.73 (dd, J=8.7, 2.1 Hz, 1H), 7.64-7.57 (m, 1H), 7.57-7.40 (m,4H), 7.21 (d, J=7.5 Hz, 1H), 5.79 (dd, J=15.3, 6.0 Hz, 1H), 5.49 (ddd,J=15. 3, 8.7, 1.2 Hz, 1H), 4.54-4.44 (m, 1H), 4.14-4.04 (m, 1H),3.66-3.52 (m, 1H), 3.00-2.85 (m, 3H), 2.60-2.10 (m, 9H), 1.90-1.60 (m,3H).

EXAMPLE 32(k)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.43 (Chloroform:Methanol=9:1); NMR: δ 8.31 and 8.24 (s, 1H),8.08 (d, J=7.8 Hz, 1H), 7.82-7.74 (m, 1H), 7.64-7.56 (m, 1H), 7.48(t,J=7.8 Hz, 1H), 7.44-7.34 (m, 3H), 5.89 (dd, J=15.6, 4.5 Hz, 1H), 5.63(dd, J=15.6, 7.5 Hz, 1H), 4.65-4.55 and 4.55-4.45 (m, 1H), 4.20-4.05 (m,1H), 3.55-3.40 (m, 1H), 3.30-3.10 (m, 1H), 3.30 (dd, J=13.8, 5.1 Hz,1H), 2.89 (dd, J=13.8, 8.7 Hz, 1H), 2.75-2.15 (m, 9H), 1.95-1.85 (m,2H), 1.80-1.60 (m, 1H).

EXAMPLE 32(l)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.38 (Chloroform:Methanol=9:1); NMR: δ 8.14 (s, 1H), 8.09 (d,J=8.1 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.56-7.32(m, 4H), 5.88 (dd, J=15.0, 5.1 Hz, 1H), 5.61 (ddd, J=15.0, 8.7, 1.5 Hz,1 H), 4.60-4.45 (m, 1H), 4.20-4.05 (m, 1H), 3.55-3.40 (m, 1H), 3.25-3.05(m, 1H), 3.01 (dd, J=13.8, 4.8 Hz, 1H), 2.88 (dd, J=13.8, 8.7 Hz, 1H),2.70-2.10 (m, 9H), 1.96-1.82 (m, 2H), 1.80-1.60 (m, 1H).

EXAMPLE 32(m)(15α-9-Oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.40 (Dichloromethane:Methanol:Acetic Acid=9:1:0.1); NMR: δ8.05-8.00 (m, 2H), 7.93-7.82 (m, 3H), 7.71 (dd, J=8.4, 1.8 Hz, 1H), 7.61(d, J=7.8 Hz, 1H), 7.56-7.47 (m, 4H), 7.42 (t, J=7.8 Hz, 1H), 7.19 (d,J=7.8 Hz, 1H), 5.84 (dd, J=15.3, 5.7 Hz, 1H), 5.52 (dd, J=15.3, 8.7 Hz,1H), 4.49 (q, J=6.0 Hz, 1H), 4.15-4.05 (m, 1H), 3.75-3.65 (m, 1H),3.35-3.05 (m, 3H), 2.95 (dd, J=7.2, 3.3 Hz, 2H), 2.50-2.10 (m, 3H),1.80-1.60 (m, 1H).

EXAMPLE 32(n)(15α)-9-Oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.36 (Dichloromethane:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.45and 8.32 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.90-7.82 (m,1H), 7.64-7.58 (m, 1H), 7.50-7.36 (m, 4H), 5.94 (dd, J=15.6, 4.5 Hz,1H), 5.78 (dd, J=Hz, 1H), 4.70-4.50 (m, 1H), 4.15 (q, J=7.2 Hz, 1H),3.60-3.20 (m, 4H), 3.00 (dd, J=14.4, 4.2 Hz, 1H), 2.85 (dd, J=14.4, 9.0Hz, 1H), 2.50-2.15 (m, 3H), 1.85-1.70 (m, 1H).

EXAMPLE 32(o)(15α)-9-Oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.37 (Dichloromethane:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.29(s, 1H), 8.20-8.14 (m, 1H), 8.11 (s, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.79(d, J=7.8 Hz, 1H), 7.60-7.30 (m, 4H), 5.90 (dd, J=15.3, 3.9 Hz, 1H),5.71 (dd, J=15.3, 9.0 Hz, 1 H), 4.60-4.45 (m, 1H), 4.20-4.05 (m, 1H),3.60-3.15 (m, 4H), 2.98 (dd, J=14.1, 4.5 Hz, 1H), 2.83 (dd, J=14.1, 9.0Hz, 1H), 2.50-2.10 (m, 3H), 1.85-1.70 (m, 1H).

EXAMPLE 32(p)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.36 (Chloroform:Methanol=9:1); NMR: δ 1.79 (m, 3 H) 2.72 (m, 13H) 3.59 (m, 1 H) 4.12 (m, 1 H) 4.49 (m, 1H) 4.78 (m, 4 H) 5.55 (dd,J=15.66, 8.79 Hz, 1 H) 5.81 (dd, J=15.66, 5.49 Hz, 1 H) 6.57 (m, 2 H)7.33 (m, 6 H).

EXAMPLE 32(q)(15α,13E)-9-Oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoicacid

TLC: Rf0.40 (Chloroform:Methanol=9:1); NMR: δ 2.09 (m, 13 H) 2.90 (m, 3H) 3.54 (m, 1 H) 4.07 (m, 1 H) 4.48 (m, 1 H) 5.46 (ddd, J=15.38, 8.79,1.10 Hz, 1 H) 5.78 (dd, J=15.38, 5.77 Hz, 1 H) 6.60 (m, 1 H) 7.14 (m, 1H) 7.25 (m, 2 H) 7.46 (m, 4 H) 7.84 (m, 1 H) 8.35 (brs., 1 H).

EXAMPLE 32(r)(15α)-9-Oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.38 (Dichloromethane:Methanol:Acetic Acid=9:1:0.1); NMR: δ 8.04(s, 1H), 7.70-7.00 (m, 5H), 6.60-6.40 (m, 3H), 6.00-5.75 (m, 1H),5.65-5.50 (m, 1H), 4.64 (s, 4H), 4.50-4.40(m, 1H), 4.20-4.10 (m, 1H),3.80-3.60 (m, 1H), 3.50-3.00 (m, 3H), 3.00-2.75 (m, 2H), 2.50-2.10 (m,3H), 1.85-1.65 (m, 1H).

EXAMPLE 32(s)(15α)-9-Oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane

TLC: Rf0.36 (Dichloromethane:Methanol:Acetic Acid=9:1:0.1); NMR(CD₃OD):δ 10.47 (s, 1H), 8.17 and 8.14 (s, 1H), 7.80-7.74 (m, 1H), 7.50-7.22 (m,6H), 7.14-7.05 (m, 1H), 6.50-6.46 (m, 1H), 5.74 (dd, J=15.0, 6.9 Hz,1H), 5.28 (dd, J=15.0, 9.0 Hz, 1H), 4.45-4.30 (m, 1H), 4.30-4.15 (m,1H), 3.55-3.45 (m, 1H), 3.30-3.20 (m, 1H), 3.20-2.70 (m, 4H), 2.35-2.00(m, 3H), 1.70-1.50 (m, 1H).

FORMULATION EXAMPLE 1

The following compounds were admixed in conventional method and punchedout to obtain 100 tablets each containing 0.5 mg of active ingredient.(15α,13E)-9-Oxo-15-hydroxy-16-  250 mg (3-methoxymethylphenyl)- (activeingredient 50 mg) 17,18,19,20-tetranor-8-azaprost-13- enoicacid.α-cyclodextrin Carboxymethylcellulose calcium  200 mg Magnesiumstearate  100 mg Micro crystalline cellulose  9.2 g

FORMULATION EXAMPLE 2

The following components were admixed in a conventional method, and thesolution was sterilized in a conventional method, placed 1 ml portionsinto ampoules and freeze-dried in a conventional method to obtain 100ampoules each containing 0.2 mg of active ingredient.(15α,13E)-9-Oxo-15-hydroxy-16- 100 mg (3-methoxymethylphenyl)- (activeingredient 20 mg) 17,18,19,20-tetranor-8-azaprost-13- enoicacid.α-cyclodextrin Mannit  5 g Distilled water 100 ml

FORMULATION EXAMPLE 3

Polylactate-glycolate copolymer (abbreviated as PLGA)(polylactate:glycolate=1:1 (mol %), weight-average molecular weight80,000, 90 mg, Mitsui chemical Co., Ltd.) and solution of the compoundof the present invention (10 mg) in methylene chloride (3 mL) wereprepared. To 0.1% polyvinylalcohol (Nacalai Tesque) solution (300 ml)stirred with 6000 rpm by using TK robomix (Tokusyukika,MARK II 2.5type), the solution prepared above was added, and the mixture wasstirred for 2 minutes at room temperature to make O/W emulsion. This O/Wemulsion was stirred for 3 hours at room temperature, volatilisemethylene chloride. After oil layer was solidified, the residue wascentrifugated for 10 minutes with 1000 rpm by using centrifugal machine(Hitachi, 05PR-22). After removing supernatant, the residue wasdispersed with distilled water for injection (35 mL), it wascentrifugated for 10 minutes with 1000 rpm by using centrifugal machineagain (twice), rinsed the sample to remove free drug etc. Finally, afterremoving a supernatent and drying a precipitate under reduced pressuremicrosphere was prepared.

The compounds of the present invention which were used for thismicrosphere pharmaceutical were showed in the following.

-   -   Formulation Example 3(1): Example 18    -   Formulation Example 3(2): Example 16(f)    -   Formulation Example 3(3): Example 16(e)        Test of Formulation 1:

The microsphere prepared in Formulation Examples 3(1) and 3(2) was addedby acetonitrile solution containing proper internal standard compoundand ultrasonicated to disolve. Content of the compound in the solutionwas determined by using HPLC, then the rate of inclusion of the compoundin microsphere was calculated by the equation as shown below.The rate of inclusion of the compound=Measured content/Theoreticalcontent multiplied by 100

The rates of the Formulation Examples 3(1), 3(2) and 3(3) are 93%, 100%and 96% each.

Test of Formulation 2:

The microsphere prepared in Formulation Examples 3(1) was suspended insaline (prepared 10 mg/kg as content of the compound). The suspensionwas administered into regio cervicalis posterior of SD-strain male ratby subcutaneous injection. Blood samples are collected at regular timeintervals after administration under anesthesia with ether. And plasmaseparated from the blood was solid-phase extracted, and theconcentration was determined by using liquid chromatograph massspectrometer (LC/MS/MS).

It was confirmed that the blood concentration of the compound wassustained at the day of 21.

Pharmacological Activity of the Compounds of the Invention:

For example, the pharmacological activities of the compounds of theinvention were confirmed in experiments performed in a laboratory usingthe cells which express prostanoid receptor sub-types.

(i) Experiment for Receptor-Binding Using Cells which Express ProstanoidReceptor Sub-Types

According to the method of Sugimoto et al. (J. Biol. Chem., 267,6463-6466 (1992)), CHO cells which expressed prostanoid receptorsub-types (murine EP₁, EP₂, EP_(3α), and EP₄, respectively) wereprepared and used as membrane authentic samples.

A reaction solution (200 μl) containing the prepared membrane fraction(0.5 mg/ml) and ³H-PGE₂ was incubated at room temperature for 1 hour.The reaction was terminated with ice cold buffer (3 ml), and thereaction mixture was filtered under suction through a glass filter(GF/B), on which the binding ³H-PGE₂ was trapped, and the bindingradioactivity was measured by means of a liquid scintillator.

The Kd value was obtained from the Acatchard plots [Ann. N.Y. Acad.Sci., 51, 660 (1949)]. Non-specific binding was obtained as the bindingin the presence of an excess amount (2.5 μM) of unlabelled PGE₂.Measurement of the binding inhibition for ³H-PGE₂ with the compounds ofthe invention was performed by adding ³H-PGE₂ (2.5 nM) and a series ofconcentrations of the compound of the invention. In this reaction, thefollowing buffer was used in all cases.

-   -   Buffer: 10 mM potassium phosphate (pH 6.9), 1 mM EDTA, 10 mM        MgCl₂, and 0.1M NaCl.

Dissociation constant Ki (μM) of each compound was calculated from thefollowing equation.Ki=IC ₅₀/(1+([C]/Kd))

The binding activities of the compounds of the invention to the EP₄receptor are shown in Table 121. TABLE 121 Example Dissociation ConstantKi (nM) 2 (pp) 0.24 3 (e) 0.71(ii) Activity of EP₄ Receptor Agonist

Experiment for measurement of the activity of an EP₄ receptor agonistwith the cells expressing prostanoid receptor sub-types

According to the method of Nishigaki et al. (FEBS left., 364, 339-341(1995)), CHO cells which expressed mouse EP₄ receptor sub-types wereprepared, inoculated on a 24-well microplate at 10⁵ cells/well, andincubated for 2 days for use in the experiment. Each well was washedwith 500 μl of MEM (minimum essential medium), added 450 μl of an assaymedium (MEM containing 1 mmol/L of IBMX and 1% BSA), and incubated at37° C. for 10 minutes. Then, 50 μl of a solution containing PGE₂ aloneor PGE₂ and a test compound was added to start the reaction, which wasconducted at 37° C. for 10 minutes and terminated with addition of 500μl of ice-cold trichloroacetic acid (10% w/v). The reaction mixture wasonce treated by freezing (−80° C.) and thawing, and the cells wereremoved with a scraper and centrifuged at 13,000 rpm for 3 minutes togive a supernatant, of which the AMP concentration was determined with acAMP assay kit. That is, a buffer solution provided for the [¹²⁵I]cAMPassay kit (Amersham) was added to 125 μl of the above supernatant to be500 μl, which was mixed with 1 ml of 0.5 mol/Ltri-n-octylamine/chloroform solution to eliminate trichloroacetic acidcontained in the chloroform layer. The aqueous layer as a sample wasmeasured to determined the cAMP amount contained in the sample accordingto the method as described in an instruction provided in the [¹²⁵I]cAMPassay kit.

The agonistic effect (EC₅₀ value) of the compounds of the invention wasdetermined by calculating 50% productivity of cAMP when the maximumeffect of PGE₂ alone was regarded as 100%.

As a result, the compounds of the invention were found to have asignificant and potent activity as EP₄ receptor agonist.

(iii) Inhibitive Effect for TNF-α Production

In male SD rats, LPS (10 μg/2 ml/kg) was injected through the tail vein,and after a lapse of 90 minutes the blood was collected in a heparinizedcondition from the abdominal vena cava to prepare the plasma. The amountof TNF-α in the plasma was determined by an ELISA kit (Rat TNF-αImmunoassay kit; Biosource). The compound of the invention was dissolvedin an equimolar amount of 0.02 mole/L sodium hydroxide solution, dilutedwith distilled water, and orally given 30 minutes before administrationof LPS. The concentration at which the production of TNF-α was inhibitedby 50% was regarded as the effective concentration (IC₅₀) when theplasma TNF-α concentration in a control group (LPS-treated but nocompound given) was 100%. As a result, the compound of the inventionshowed a significant effect for inhibition of TNF-α production.

(iv) Inhibitive Effect for Chronic Articular Rheumatism

(1) Arthritis Induced by Collagen in Rats

Experiment was performed according to the method of Osterman et al.(Inflamm. Res., 44, 258-263). An inducing agent (an emulsion prepared byadding an equal volume of physiological saline and 2 equivalent volumeof incomplete Freund adjuvant to 0.3% solution of type II collagen ofbovine origin) 0.1 ml each was applied intracutaneously to the 4 sitesof the back of a female DA/Slc rat. After a lapse of 1 week, the sameinducing agent was further applied intracutaneously to the tail root toinduce arthritis. At 27 days the limbs were scored responding to thedegree of redness and edema and assessed as 30 was regarded as fullscores. The compound of the invention was dissolved in an equimolaramount of 0.02 mole/L sodium hydroxide solution, diluted with distilledwater, and orally given 3 times a day from the next day of the firstadministration of inducer.

Result:

The effect of the compound of the invention for collagen-inducedarthritis in rats is shown in Table 122. TABLE 122 Arthritic ScoreCompound Dose (Means ± SE) Example 2 vehicle 24.6 ± 1.0  1000 μg/kg 17.3 ± 1.5* Example 3 (b) vehicle 24.6 ± 1.0  300 μg/kg 19.3 ± 1.4*Example 3 (l) vehicle 27.0 ± 1.2  100 μg/kg 16.3 ± 3.0* Example 3 (kk)vehicle 23.4 ± 3.0  100 μg/kg 11.9 ± 3.6* Example 4 (h) vehicle 27.0 ±1.2  300 μg/kg  9.8 ± 1.9**p < 0.05

As a result, significant improvement of the condition of arthritis andinhibition of the increase of limb volume (edema) were recognized byadministration of the compounds of the invention in comparison withthose of a control group (distilled water was orally given 3 times aday).

(2) Arthritis Induced by Cocktail Antibodies in Mice

A cocktail of antibodies to type II collagen was intravenously appliedto male DBA/1JNCrj mice at a dose of 2 mg/0.5 ml/mouse. After a lapse of3 days, lipopolysaccharide was intraperitoneally applied at a dose of 25μg/0.1 ml/mouse to induce arthritis. At 10 days the limbs wererespectively scored responding to the degree of redness and edema andassessed as 4 was regarded as full scores. The compound of the inventionwas dissolved in an equimolar amount of 0.02 mole/L sodium hydroxidesolution, diluted with distilled water, and orally given 3 times a dayfrom 30 minutes before the administration of lipopolysaccharide.

As a result, significant improvement of the condition of arthritis andinhibition of the increase of limb volume (edema) were recognized byadministration of the compounds of the invention in comparison withthose of a control group (distilled water was orally given 3 times aday).

(v) Effect on the Promotion of Osteogenesis 1

Female SD rats (11 weeks of age; average weight 271 g) were employed in5 rats for each group. Rat was cut open at the lateral abdomen underanesthetization with pentobarbital to remove the ovary and then sutured.In a sham group, incision and suture were made but no removal of theovary was made.

From 6 days after the surgical operation, the compound of the invention(dissolved in an equimolar amount of 0.02 mole/L sodium hydroxidesolution, and diluted with distilled water) were orally give 3 times aday for 2 months. To the control group and the sham group was givenphysiological saline. After termination of the test, the animals of eachgroup were killed and subjected to autopsy. The bone density of thecancellous region of left thigh bone was measured by means of anapparatus for measuring the bone density of peripheral bone (XCT-960A,Norland/Stratech).

As a result, the compound of the invention significantly increased thebone density when compared with a control group (no administration).

(vi) Effect on the Promotion of Osteogenesis 2

Using beagle/CSK dogs of approximately 6 months of age, the effect onthe promotion of osteogenesis can be examined.

The compound of the invention was dissolved in physiological saline andorally administered over 4 weeks. To a control group was give an equalvolume of physiological saline. After completion of the administration,the dogs were killed, subjected to autopsy, and the area and density ofbone were measured.

(1) Measurement of Bone Area

The removed thigh bone was fixed with 10% buffered formalin solution andcut in round slices perpendicularly to the bone axis in 10 mm width atthe center position of 25 mm from the trochlear fossa; the surface nearthe epiphysis was photographed with a camera at a certain distance, andthe picture was sent into a computer to measure the bone surface byimage analysis.

(2) Measurement of Bone Density

The sample of 1 cm in width used in (1) was taken radiographs in sideview, and the picture was sent into a computer to measure the radiationdose per unit area in the area of a certain width to obtain the bonedensity (Micro Focus X-Ray Enlargement Camera System μFX-1000(FUJIFILM)).

(vii) Effect of Accelerating Cure of Bone Fracture 1

This can be achieved according to the method of Markel et al. (J. Boneand Joint Surgery, 73A, 914-923, 1991). Using beagle/CSK dogs ofapproximately 6 months of age, the femoral tibia is fractured underanesthesia and taken radiographs periodically for 3 months to assess theprogress of cure. Thus, the effect of accelerating cure of bone fracturecan easily be judged. The compound of the invention is orallyadministered everyday. To a control group is given distilled water. Whenthe effect of acceleration of cure is recognized, the tibia is removedand the bone density and strength can be measured to further assessquantitatively.

(viii) Inhibitive Effect for Gastric Ulcer

To SD rats was orally administered 20 mg/kg of indomethacin to inducegastric ulcer. After a lapse of 6 hours, the stomach was removed tomeasure the ulcerous area of mucosa. The compound of the invention wasorally administered 30 minutes before administration of indomethacin. Asa result, the compound of the invention significantly reduced theulcerous area when compared to the control group (no administration).

(ix) Effect of Accelerating Cure of Bone Fracture

According to the methods of R. Sakai (Bone, 25, 191-196 (1999)), H.Kawaguchi (Endocrinology, 135, 774-781 (1994)) and T. Hoshino (J. BiomedMater Res., 51 229-306 (2000)), a bone fracture model was prepared withmale IGS rats of 8 weeks of age. Hair of the left hind-limb of a rat wascut under anesthetization with pentobarbital Na, and Viccillin S 500(500 mg potency) (Meiji Seika) was intramuscularly injected at a dose of10 mg potency/100 μl distilled water/body. Then, the skin on the fibula(from the back of knee joint to tendo Achillis) was incised to ablatethe muscular tissue and expose the fibula. The fibula was cut offapproximately at the central position to make a fracture portion, whichwas then restored to its former condition, and the incised portion wasclosed by suture with disinfection by iodine tincture/disinfectantethanol. After making the fracture portion and before closing the woundof operation, a physiological saline solution containing 0.2% Tween 80microsphere (containing 0.3 mg/kg as an active drug; about 60 μl)prepared in Formulation Example 3(1) was added only once. In addition,Compound (1) as a control for comparison was infused continuously for 2hours twice a day through a catheter attached to the carotid artery.This was made until the last day of the experiment. At the 21st day ofthe experiment, the rats were subjected to euthanasia with CO₂, and theconnective tissue of the hind-limbs, including muscle, was eliminated toobtain both of the fibulae. The recovered fibulae were taken radiographsto assess development of the cure of fracture based on the presence of afracture line and callus formation, and the density and strength of thebone around the fracture portion were measured.

(1) Measurement of the Bone Density of the Callus Region Using a MicroFocus X-Ray Enlargement Camera System

The bone density of the callus region at the fracture position of therecovered fibula was measured referring to the reports of C. Matsumoto(Calcif Tissue Int, 55, 324-329 (1994)), Kaoru Yamazaki (Nihon Rinsyo,56, 1464-1468 (1998)), and Keiichi Nakagawa (Sentan Iryo, 4(6), (1996)).Radiophotographs were taken at 4 magnifications using a micro focusX-ray enlargement camera system (FUJIFILM)/imaging plate (BAS-IP MS2025; FUJIFILM) in a radiation condition of 40 kV tube voltage, 100 μAtube current, and radiation time 5 seconds. During photographing, aphantom for quantitative analysis of bone salt for mice (Kyoto KagakuCo.) was set together in order to make an analytical curve formeasurement of bone density. The image was read by a Bio-imagingAnalyzer BAS-1800 (FUJIFILM)/Image Reader (FUJIFILM) and processed withan Image Gauge, ver.3.1.12 (FUJIFILM). Based on the fracture line(surface) as a callus region, the region of interest (hereinaftersometimes referred to as ROI) was set at the position of 3 mm in theremote direction (ankle) and in the proximal direction (knee)respectively to calculate the bone density of each ROI from theanalytical curve obtained from the phantom for quantitative analysis ofbone salt. The bone density of the callus region at the fracture sidewas calculated from the following equation and represented bymeansastandard error (mg/cm²). $\begin{matrix}{\begin{matrix}{{Bone}\quad{density}\quad{in}} \\{{callus}\quad{region}}\end{matrix} = \left\{ \left( {\left\lbrack {{bone}\quad{density}\quad{in}\quad{proximal}\quad{callus}\quad{region}} \right\rbrack \times} \right. \right.} \\{\left. \quad A \right) + \left( {\left\lbrack {{bone}\quad{density}\quad{in}\quad{remote}\quad{callus}\quad{region}} \right\rbrack \times} \right.} \\{\left. \left. \quad B \right) \right\}/\left( {A + B} \right)} \\{{A\quad{represents}\quad{the}\quad{ROI}\quad{area}\quad{in}\quad{the}\quad{proximal}\quad{callus}\quad{region}};} \\{B\quad{represents}\quad{the}\quad{ROI}\quad{area}\quad{in}\quad{the}\quad{remote}\quad{callus}\quad{{region}.}}\end{matrix}$(2) Measurement of the Bone Strength by a Bending Test at Three Points

According to the report of T. Hoshino (J Biomed Mater Res., 51, 229-306(2000)), a bending test at three points was performed. Using an InstronUniversal Material Testing Machine Type 5544 (Instron Japan)/Merlin(Instron Japan; version 22043), fracture strength and energy absorptionwere measured in a condition of 2.5 mm/sec of bending rate and 10 mm ofsample holder width. The bone strength data was calculated as relativestrength of the non-fractured side versus the fractured side for therespective individuals and represented by means ± standard error (% ofintact).

Result:

The effect of accelerating cure of bone fracture when the fracturedportion was treated only once with microsphere (containing 0.3 mg/kg asan active drug) prepared in Formulation Example 3(1) or a reference(physiological saline containing 0.2% Tween 80) is shown in Table 123.

The effect of accelerating cure of bone fracture when the fracturedportion was treated only once with microsphere (containing 1 mg/kg as anactive drug) prepared in Formulation Example 3(3) or a reference(physiological saline containing 0.2% Tween 80) is shown in Table 123.TABLE 123 Bone Density Fracture Strength (mg/cm²) (% of intact)Formulation 60.9 ± 4.0 149.8 ± 12.4% Example 3(1) Reference (Control)39.8 ± 2.7 62.8 ± 8.5%

TABLE 124 Bone Density Fracture Strength (mg/cm²) (% of intact)Formulation 51.6 ± 3.8 114.6 ± 10.4% Example 3(3) Reference (Control)36.5 ± 2.5 55.3 ± 5.7%

The effect of accelerating cure of bone fracture when Compound (1) (50ng/kg/min) and a reference (physiological saline) were administeredintravenously for 2 hours twice a day for 21 days is shown in Table 125.TABLE 125 Bone Density Fracture Strength (mg/cm²) (% of intact) Compound42.8 ± 2.58 30.4 ± 12.4% Reference (Control) 35.2 ± 1.91 55.2 ± 9.77%

As clearly seen from Tables 123 and 124 in comparison with Table 125,the effect of accelerating cure of bone fracture when treated only oncewith microspheres which were prepared in Formulation Examples 3(1) and3(3) were much higher than that of Compound (1) which was administeredintravenously for 21 days.

(x) Inhibitive Effect on Ulcerous Colitis

7% Sodium dextran sulfate aqueous solution (hereinafter abbreviated toas SDS) was given freely to male C57BL/6 mice. From the beginning ofdrinking, the body weight and clinical score were recorded every otherday. The clinical score was calculated as the sum of diarrhea score(normal: 0; soft: 2; diarrhea: 4) and hematochezia (normal: 0; bleeding:2; heavy bleeding: 4). At 10 days after taking of the SDS aqueoussolution, the blood was collected from the vena cava under etherealanesthesia in the presence of heparin, and the hematocrit value wasmeasured by a hemocytometer. During a period of from 0 day to 10th dayafter taking of the SDS aqueous solution, the compound of the inventionwas orally administered twice a day at a dose of 10, 30, 100 or 300μg/10 ml/kg. As a result, the compound of the invention showed asignificant inhibitive effect on ulcerous colitis.

1. A pharmaceutical composition for topical administration for prevention and/or treatment of diseases associated with decrease in bone mass comprising an EP₄ agonist as an active ingredient.
 2. The pharmaceutical composition for prevention and/or treatment according to claim 1, wherein the disease associated with decrease in bone mass is primary osteoporosis, secondary osteoporosis, bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss and bone necrosis, postoperative osteogenesis, or alternative therapy for bone grafting.
 3. A sustained release formulation comprising an EP₄ agonist as an active ingredient.
 4. The formulation according to claim 3, wherein the sustained release formulation is a microsphere, a microcapsule, a nanosphere or a film.
 5. A pharmaceutical composition for prevention and/or treatment of diseases associated with decrease in bone mass, comprising the formulation described in claim 3 which is topically administered.
 6. The pharmaceutical composition for prevention and/or treatment of diseases associated with decrease in bone mass according to claim 1, wherein the EP₄ agonist is a compound possessing prostaglandin skeleton.
 7. The sustained release formulation according to claim 3, wherein the EP₄ agonist is a compound possessing prostaglandin skeleton.
 8. The pharmaceutical composition for treatment and/or prevention according to claim 1, wherein the compound possessing prostaglandin skeleton is a compound selected from the group of formula (I-1)

wherein R¹⁻¹ is hydroxy, C1-6 alkyloxy, or NR⁶⁻¹R⁷⁻¹, wherein R⁶⁻¹ and R⁷⁻¹ are each independently, hydrogen atom or C1-4 alkyl, R²⁻¹ is oxo, halogen, or O—COR⁸⁻¹, wherein R⁸⁻¹ is C1-4 alkyl, phenyl or phenyl(C1-4 alkyl), R³⁻¹ is hydrogen atom or hydroxy, R^(4a-1) and R^(4b-1) are each independently, hydrogen atom or C1-4 alkyl, R⁵⁻¹ is phenyl substituted by the group listed below: (i) 1 to 3 of C1-4 alkyloxy-C1-4 alkyl, C2-4 alkenyloxy-C1-4 alkyl, C2-4 alkynyloxy-C1-4 alkyl, C3-7 cycloalkyloxy-C1-4 alkyl, C3-7 cycloalkyl(C1-4 alkyloxy)-C1-4 alkyl, phenyloxy-C1-4 alkyl, phenyl-C1-4 alkyloxy-C1-4 alkyl, C1-4 alkylthio-C1-4 alkyl, C2-4 alkenylthio-C1-4 alkyl, C2-4 alkynylthio-C1-4 alkyl, C3-7 cycloalkylthio-C1-4 alkyl, C3-7 cycloalkyl(C1-4 alkylthio)-C1-4 alkyl or phenylthio-C1-4 alkyl or phenyl-C1-4 alkylthio-C1-4 alkyl, (ii) C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyl, C1-4 alkyloxy-C1-4 alkyl and C1-4 alkyloxy, C1-4 alkyloxy-C1-4 alkyl and hydroxy, C1-4 alkyloxy-C1-4 alkyl and halogen, C1-4 alkylthio-C1-4 alkyl and C1-4 alkyl, C1-4 alkylthio-C1-4 alkyl and C1-4 alkyloxy, C1-4 alkylthio-C1-4 alkyl and hydroxy or C1-4 alkylthio-C1-4 alkyl and halogen, (iii) haloalkyl or hydroxy-C1-4 alkyl, or (iv) C1-4 alkyl and hydroxy;

is single bond or double bond, wherein when R²⁻¹ is O—COR⁸⁻¹, C8-9 position is double bond, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
 9. The sustained release formulation according to claim 3, wherein the compound possessing prostaglandin skeleton is a compound selected from the group of formula (I-1) described in claim 8, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
 10. The pharmaceutical composition for treatment and/or prevention according to claim 1, wherein the compound possessing prostaglandin skeleton is a compound selected from the group of formula (I-2)

wherein R¹⁻² is (1) —CO—(NH-amino acid residue-CO)_(m-2)—OH, (2) —COO—Y²—R⁹⁻², (3) —COO—Z¹⁻²—Z²⁻²—Z³⁻², wherein Y² is bond or C1-10 alkylene, R⁹⁻² is (1) phenyl or (2) biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom, Z¹⁻² is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3) C2-15 alkynylene, Z²⁻² is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR¹¹⁻²—, (5) —NR¹²⁻²CO—, (6) —O—, (7) —S—, (8) —SO—, (9) —SO₂—, (10) —NR¹³⁻²—, (11) —NR¹⁴⁻²CONR¹⁵⁻²—, (12) —NR¹⁶⁻²COO—, (13) —OCONR¹⁷⁻²— or (14) —OCOO—, Z³⁻² is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl, (4) C2-15 alkynyl, (5) ring1² or (6) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR¹⁸⁻²— or ring1², ring1² is (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or (2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated, R¹¹⁻², R¹²⁻², R¹³⁻², R¹⁴⁻², R¹⁵⁻², R¹⁶⁻², R¹⁷⁻² and R¹⁸⁻² are each independently, hydrogen atom or C1-15 alkyl, R¹¹⁻² and Z³⁻² may be taken together with the nitrogen atom to which they are attached to form 5 to 7 membered saturated monoheterocyclic ring, and the heterocyclic ring may contain another one hetero atom selected from oxygen, nitrogen and sulfur atom, ring1² and saturated monoheterocyclic ring formed by R¹¹⁻², Z³⁻² and the nitrogen atom to which Z³⁻² is attached may be substituted by 1-3 group(s) selected from (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 alkynyl and (4) C1-10 alkyl substituted with C1-10 alkoxy, C1-10 alkylthio or C1-10 alkyl-NR¹⁹⁻², R¹⁹⁻² is hydrogen atom or C1-10 alkyl, m-2 is 1 or 2, other symbols are same meaning as defined in claim 8, or a non-toxic salt thereof, or cyclodextrin clathrate thereof.
 11. The sustained release formulation according to claim 3, wherein the compound possessing prostaglandin skeleton is a compound selected from the group of formula (I-2) described in claim 10, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
 12. The pharmaceutical composition for treatment and/or prevention according to claim 1, wherein the compound possessing prostaglandin skeleton is a compound selected from the group of formula (I-3)

wherein

is (1) single bond or (2) double bond, R¹⁹⁻³ and R²⁰⁻³ are each independently, (1) hydrogen atom, (2) C1-10 alkyl or (3) halogen atom, T³ is (1) oxygen atom or (2) sulfur atom, X³ is (1) —CH₂—, (2) —O— or (3) —S—, A³ is A¹⁻³or A²⁻³, A¹⁻³ is (1) C2-8 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl, (2) C2-8 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or (3) C2-8 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl, A²⁻³ is -G¹⁻³-G²⁻³-G³⁻³-, G¹⁻³ is (1) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl, (2) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or (3) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl, G²⁻³ is (1) —Y³—, (2) -(ring 1³)-, (3) —Y³-(ring1³)-, (4) -(ring1³)-Y³— or (5) —Y³—(C1-4 alkylene)-(ring1³)-, Y³ is (1) —S—, (2) —SO—, (3) —SO₂—, (4) —O— or (5) —NR—¹⁻³—, R¹⁻³ is (1) hydrogen atom, (2) C1-10 alkyl or (3) C2-10 acyl, G³⁻³ is (1) bond, (2) C1-4 straight-chain alkylene optionally substituted by 1-2 C1-4 alkyl, (3) C2-4 straight-chain alkenylene optionally substituted by 1-2 C1-4 alkyl or (4) C2-4 straight-chain alkynylene optionally substituted by 1-2 C1-4 alkyl, D³ is D¹⁻³ or D²⁻³, D¹⁻³ is (1) —COOH, (2) —COOR²⁻³, (3) tetrazol-5-yl or (4) CONR³⁻³SO₂R⁴⁻³, R²⁻³ is (1) C1-10 alkyl, (2) phenyl, (3) C1-10 alkyl substituted by phenyl or (4) biphenyl, R³⁻³ is (1) hydrogen atom or (2) C1-10 alkyl, R⁴⁻³ is (1) C1-10 alkyl or (2) phenyl, D²⁻³ is (1) —CH₂OH, (2) —CH₂OR⁵⁻³, (3) hydroxy, (4) —OR⁵⁻³, (5) formyl, (6) —CONR⁶⁻³R⁷⁻³, (7) —CONR⁶⁻³SO₂R⁸⁻³, (8) —CO—(NH-amino acid residue-CO)_(m-3)—OH, (9) —O—(CO-amino acid residue-NH)_(m-3)—H, (10) —COOR⁹⁻³, (11) —OCO—R¹⁰⁻³, (12) —COO—Z¹⁻³—Z²⁻³—Z³⁻³, (13)

R⁵⁻³ is C1-10 alkyl, R⁶⁻³ and R⁷⁻³ are each independently, (1) hydrogen atom or (2) C1-10 alkyl, R⁸⁻³ is C1-10 alkyl substituted by phenyl, R⁹⁻³ is (1) C1-10 alkyl substituted by biphenyl optionally substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom or (2) biphenyl substituted by 1-3 C1-10 alkyl, C1-10 alkoxy or halogen atom, R¹⁰⁻³ is (1) phenyl or (2) C1-10 alkyl, m-3 is 1 or 2, Z¹⁻³ is (1) C1-15 alkylene, (2) C2-15 alkenylene or (3) C2-15 alkynylene, Z²⁻³ is (1) —CO—, (2) —OCO—, (3) —COO—, (4) —CONR¹¹⁻³—, (5) —NR¹²⁻³CO—, (6) —O—, (7) —S—, (8) —SO—, (9) —SO₂—, (10) —NR¹³⁻³—, (11) —NR¹⁴⁻³CONR¹⁵⁻³—, (12) —NR¹⁶⁻³COO—, (13) —OCONR¹⁷⁻³— or (14) —OCOO—, Z³⁻³ is (1) hydrogen atom, (2) C1-15 alkyl, (3) C2-15 alkenyl, (4) C2-15 alkynyl; (5) ring2³ or (6) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio, C1-10 alkyl-NR¹⁸⁻³— or ring2³, R¹¹⁻³, R¹²⁻³, R¹³⁻³, R¹⁴⁻³, R¹⁵⁻³, R¹⁶⁻³, R¹⁷⁻³ and R¹⁸⁻³ are each independently, (1) hydrogen atom or (2) C1-15 alkyl, R¹¹⁻³ and Z³⁻³ may be taken together with the nitrogen atom to which they are attached to form 5 to 7 membered saturated monoheterocyclic ring, and the heterocyclic ring may contain other one hetero atom selected from oxygen, nitrogen and sulfur atom, E³ is E¹⁻³ or E²⁻³, E¹⁻³ is (1) C3-7 cycloalkyl or (2) ring3³, E²⁻³ is (1) C3-7 cycloalkyl, (2) ring4³ or (3) ring5³, ring1³ and ring5³are optionally substituted by 1-3 R²¹⁻³ and/or R²²⁻³, ring3³ is optionally substituted by 1-2 R²¹⁻³, C3-7 cycloalkyl represented by E²⁻³ is substituted by one of R²¹⁻³ or R²²⁻³, and optionally substituted by another 1-2 R²¹-³ and/or R²²⁻³, ring4³ is substituted by one of R²²⁻³, optionally substituted by another 1-2 R²¹⁻³ and/or R²²⁻³, and optionally substituted by heterocyclic ring formed by R¹¹⁻³, Z³⁻³ and the nitrogen to which Z³⁻³ is attached or ring2³ may be substituted by R²³⁻³, R²¹⁻³ is (1) C1-10 alkyl, (2) C1-10 alkoxy, (3) halogen atom, (4) nitro, (5) C1-10 alkyl substituted by 1-3 halogen atom(s) or (6) phenyl, R²²⁻³ is (1) C2-10 alkenyl, (2) C2-10 alkynyl, (3) C1-10 alkylthio, (4) hydroxy, (5) —NR²⁴⁻³R²⁵⁻³, (6) C1-10 alkyl substituted by C1-10 alkoxy, (7) C1-10 alkyl substitute 10 alkoxy substituted by 1-3 halogen atom(s), (8) C1-10 alkyl substituted by —NR²⁴⁻³R²⁵⁻³, (9) ring6³, (10)-O-ring7³, (11) C1-10 alkyl substituted by ring7³, (12) C2-10 alkeny substituted by ring7³, (13) C2-10 alkynyl substituted by ring7³, (14) C1-10 alkoxy substituted by ring 7³, (15) C1-10 alkyl substituted by —O-ring7³, (16) —COOR²⁶⁻³ or (17) C1-10 alkoxy substituted by 1-3 halogen atom(s)(s), R²⁴⁻³, R²⁵⁻³ and R²⁶⁻³ are each independently, (1) hydrogen atom or (2) Cl-10 alkyl, R²³⁻³ is (1) C1-15 alkyl, (2) C2-15 alkenyl, (3) C2-15 alkynyl or (4) C1-10 alkyl substituted by C1-10 alkoxy, C1-10 alkylthio or C1-10 alkyl-NR²⁷⁻³—, R²⁷⁻³ is (1) hydrogen atom or (2) C1-10 alkyl, ring1³, ring2³, ring5³, ring6³ and ring7³ are (1) C3-15 mono-, bi- or tri-carbocyclic aryl which may be partially or fully saturated or (2) 3 to 15 membered mono-, bi- or tri-heterocyclic aryl containing 1 to 4 hetero atom selected from oxygen, nitrogen and sulfur atom(s) which may be partially or fully saturated, ring3³ and ring4³ are (1) thienyl, (2) phenyl or (3) furyl, ring6³ and ring7³ may be substituted by 1-3 R²⁸⁻³, R²¹⁻³ is (1) C1-10 alkyl, (2) C2-10 alkenyl, (3) C2-10 alkynyl, (4) C1-10 akloxy, (5) C1-10 alkyl substituted by C1-10 alkoxy, (6) halogen atom, (7) hydroxy, (8) C1-10 alkyl substituted by 1-3 halogen atom(s) or (9) C1-10 alkyl substituted by C1-10 alkoxy substituted by 1-3 halogen atom(s), and wherein (1) when T³ is oxygen atom, X³ is CH₂—, A³ is A¹⁻³, and D3 is D¹⁻³, E³ is E²⁻³ (2) ring5³ is not C3-7 cycloalkyl, phenyl, thienyl nor furyl, (3) ring6³ is phenyl, then phenyl have at least one R²⁸⁻³, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof
 13. The sustained release formulation according to claim 3, wherein the compound possessing prostaglandin skeleton is a compound selected from the group of formula (1-3) described in claim 12, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof
 14. A prostaglandin derivative of formula (I-2)

wherein all symbols have the same meaning as defined in claim 10, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof
 15. A compound selected from the group of formula (I-3)

wherein all symbols have the same meaning as defined in claim 12, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
 16. A compound selected from the group consisting of (1) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (2) (15α,13E)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (3) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (4) (15α,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (5) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (6) (15α,13E)-9-oxo-15-hydroxy-16-(4-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (7) (15α,13E)-9-oxo-15-hydroxy-16-(2-methylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (8) (15α,13E)-9-oxo-15-hydroxy-16-(2-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (9) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (10) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (11) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (12) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (13) (15α,13E)-9-oxo-15-hydroxy-16-(3,5-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (14) (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (15) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethoxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (16) (15α,13E)-9-oxo-15-hydroxy-16-(3-isopropyloxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (17) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (18) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (19) (15α,13E)-9-oxo-15-hydroxy-16-(3,5-dimethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (20) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (21) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (22) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (23) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (24) (15α)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-8-azaprostanoic acid, and (25) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoic acid 3-phenylphenyl ester, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
 17. The compound according to claim 15, wherein —Y³— group in A³ group of a compound of formula (I-3) is —S— group.
 18. The compound according to claim 14, which is a compound selected from the group consisting of (1) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-nonanoyloxyethyl ester, (2) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid pivaloyloxymethyl ester, (3) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 1-cyclohexyloxycarbonyloxyethyl ester, (4) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid N,N-diethylaminocarbonylmethyl ester, (5) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-acetyloxyethyl ester, (6) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid benzoylmethyl ester, (7) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid isopropyloxycarbonylmethyl ester, (8) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid N,N-diethylaminocarbonyloxymethyl ester, (9) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid t-butyloxycarbonylmethyl ester, (10) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 1-isopropyloxycarbonylethyl ester, (11) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 1-benzoylethyl ester, (12) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid methoxycarbonylmethyl ester, (13) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-tridecanoyloxyethyl ester, (14) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-heptanoyloxyethyl ester, (15) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-octanoyloxyethyl ester, (16) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-decanoyloxyethyl ester, (17) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid allyloxycarbonylmethyl ester, (18) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid nonanoyloxymethyl ester, (19) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-hydroxyethyl ester, (20) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid phenyl ester, (21) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid carboxymethyl ester, (22) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid dipropylcarbamoylmethyl ester, (23) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid dibutylcarbamoylmethyl ester, (24) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 4-pentylbenzoylmethyl ester, (25) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 1,1-dimethylheptyloxycarbonylmethyl ester, (26) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid dipentylcarbamoylmethyl ester, (27) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-octyloxyethyl ester, (28) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-(2,2-dimethylpentanoyloxy)ethyl ester, (29) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 3-butoxypropyl ester, (30) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-butoxyethyl ester, (31) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-pentyloxyethyl ester, (32) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-hexyloxyethyl ester, (33) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-(2,2-dimethyloctanoyloxy)ethyl ester, (34) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-(2,2-diethylpentanoyloxy)ethyl ester, (35) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 4-(4-chlorophenyl)phenyl ester, (36) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-(adamantan-1-ylcarbonyloxy)ethyl ester, and (37) (11α,15α,13E)-9-oxo-11,15-dihydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thiaprost-13-enoic acid 2-(2,2-dipropylpentanoyloxy)ethyl ester, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof.
 19. The compound according to claim 15, which is a compound selected from the group consisting of (1) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid ethyl ester, (2) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (3) (5S,15α,13E)-5-methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (4) (15α,13E)-5,5-dimethyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (5) (15α,13E)-5,5-ethano-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (6) (5R, 15α,13E)-5-methyl-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (7) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (8) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-2,3,4,17,18,19,20-heptanor-1,5-(2,5-interthienylene)-8-azaprost-13-enoic acid, (9) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-hydroxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (10) (15α,13E)-9-oxo-15-hydroxy-16-((E)-1-propenylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (11) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-fluorophenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (12) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-fluorophenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (13) (15α,13E)-9-oxo-15-hydroxy-16-(3-(5-methylfuran-2-yl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (14) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (15) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-methoxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (16) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-hydroxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (17) (15α,13E)-9-oxo-15-hydroxy-16-(3-(3-hydroxyphenyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (18) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (19) (15α,13E)-9-oxo-15-hydroxy-16-(3-cyclopropylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (20) (13E)-9-oxo-15-hydroxy-16,16-difluoro-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (21) (15α,13E)-9-oxo-15-hydroxy-16-(3-benzyloxyphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (22) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-5,13-dienoic acid, (23) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (24) (15α,13E)-2,7-(1,3-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid, (25) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2-phenylethynyl)phenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (26) (15α,13E)-2,7-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-3,4,5,6,17,18,19,20-octanor-8-azaprost-13-enoic acid, (27) (15α,5Z,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2,6-(1,3-interphenylene)-3,4,5,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (28) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (29) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxadiazol-3-yl)thiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (30) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interfurylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (31) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienylene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (32) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(tetrazol-5-yl)thiophen-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (33) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalen-1-yl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (34) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (35) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (36) (15α,13E)-9-oxo-15-hydroxy-16-(3-cyclopropyloxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (37) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (38) (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (39) (15α,13E)-9-oxo-15-hydroxy-16-cyclopentyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (40) (15α,13E)-9-oxo-15-hydroxy-16-(thiophen-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (41) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (42) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (43) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (44) (15α,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (45) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (46) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (47) (15α,13E)-9-oxo-15-hydroxy-16-(naphthalen-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (48) (15α,13E)-2,3-methano-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (49) (15α,13E)-9-oxo-15-hydroxy-16-(3-t-butylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (50) (13E)-9-oxo-15-hydroxy-16α-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (51) (13E)-9-oxo-15-hydroxy-16β-methyl-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (52) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (53) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,18,19,20-8-tetranor-5-thia-8-azaprost-13-enoic acid, (54) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (55) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (56) (15β,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (57) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (58) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-4-(3-hydroxyisoxazol-5-yl)-1,2,3,17,18,19,20-heptanor-5-thia-8-azaprost-13-ene, (59) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-oxadiazol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene, (60) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-2-(5-oxo-1,2,4-thiadiazol-3-yl)-1,17,18,19,20-pentanor-5-thia-8-azaprost-13-ene, (61) (15α,13E)-1-methoxy-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-ene, (62) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (63) (15α,13E)-1-methoxy-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-ene, (64) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-(5-oxo-1,2,4-oxadiazol-3-yl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (65) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-5-thia-8-aza-10-oxaprost-13-enoic acid, (66) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoic acid, (67) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-enoic acid, (68) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylaminomethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid hydrochloride, (69) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (70) (15α,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (71) (15α,13E)-9-oxo-15-hydroxy-16-(2-methyloxazol-5-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (72) (15α,13E)-9-oxo-15-hydroxy-16-(benzofuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (73) (15α,13E)-9-oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (74) (15α,13E)-9-oxo-15-hydroxy-16-(4,5-dimethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (75) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (76) (15α,13E)-9-oxo-15-hydroxy-16-(3-nitrophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (77) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylisoxazol-5-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (78) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol, (79) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (80) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol, (81) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-8-azaprost-13-en-1-ol, (82) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (83) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (84) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (85) (15α,13E)-9-oxo-15-hydroxy-16-(3-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (86) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (87) (15α,13E)-9-oxo-15-hydroxy-16-(3-propylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (88) (15α,13E)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (89) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (90) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-difluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (91) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (92) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluoro-3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (93) (15α,13E)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (94) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-ol, (95) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(5-hydroxymethylthiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (96) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-en-1-ol, (97) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-aza-10-oxaprost-13-en-1-ol, (98) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-3,7-(2,5-interthienylene)-4,5,6,17,18,19,20-heptanor-8-azaprost-13-en-1-ol, (99) (15α,13E)-9-oxo-15-hydroxy-16-(3-ethyl-4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (100) (15α,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (101) (15α,13E)-9-oxo-15-hydroxy-16-(5-ethylfuran-2-yl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-ol, (102) (15α)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprostanoic acid ethyl ester, (103) (15α)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprostanoic acid, (104) (15α)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprostanoic acid, (105) (15α)-9-oxo-15-hydroxy-16-(3-trifluoromethylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprostanoic acid, (106) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid N-mesylarmide, (107) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid N-phenylsulfonylamide, (108) (15α,13E)-9-oxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid N-benzylsulfonylamide, (109) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid N-benzylsulfonylamide, (110) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(5-benzylsulfonylcarbamoylthiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (111) (15α,13E)-9-thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester, (112) (15α,13E)-9-thioxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (113) (15α,13E)-9-thioxo-15-hydroxy-16-(3-methoxymethylphenyl)-17,18,19,20-tetranor-8-azaprost-13-enoic acid, (114) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl t-butoxycarbonylglycylglycinate, (115) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl glycylglycinate monohydrochloride, (116) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl glycinate methanesulfonic acid salt, (117) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl tryptophanate bis-trifluoroacetic acid salt, (118) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-yl tyrosinate trifluoroacetic acid salt, (119) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid isopropyloxycarbonylmethyl ester, (120) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid dimethylaminocarbonylmethyl ester, (121) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid ethyl ester, (122) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid butyl ester, (123) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,5-(2,5-interthienylene)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-en-1-al, (124) (15α,13E)-9-oxo-15-hydroxy-16-(3-chlorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-en-1-al, (125) (15α,13E)-9-oxo-15-hydroxy-16-(3-aminophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (126) (15α,13E)-1-benzoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene, (127) (15α,13E)-1-butanoyloxy-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene, (128) (15α,13E)-1-(2-aminoacetyloxy)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-ene trifluoromethanesulfonic acid salt, (129) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-pentanoyloxyethyl ester, (130) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoic acid 4-phenylbenzyl ester, (131) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-17,18,19,20-tetranor-8-azaprost-13-enoic acid 2-dimethylaminoethyl ester hydrochloride, (132) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-hexanoyloxyethyl ester, (133) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-heptanoyloxyethyl ester, (134) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-octanoyloxyethyl ester, (135) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid N-heptanoyl-N-methylcarbamoylmethyl ester, (136) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid (4-hexylpiperazin-1-yl)carbonylmethyl ester, (137) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid N-ethyl-N-(2-diethylaminoethyl)carbamoylmethyl ester, (138) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2-(dipropylamino)acetyloxy)ethyl ester, (139) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2-(diethylamino)acetyloxy)ethyl ester, (140) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid nonanoyloxymethyl ester, (141) (15α,13E)-9-oxo-15-hydroxy-16-(4-aminophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (142) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (143) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-chloro-4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (144) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(4-fluoro-3-trifluoromethylphenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (145) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid ethyl ester, (146) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (147) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (148) (15α)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (149) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (150) (15α,13E)-7-(6-carboxyindol-3-yl)-9-oxo-15-hydroxy-16-(3-methylphenyl)-1,2,3,4,5,6,17,18,19,20-decanor-8-azaprost-13-ene, (151) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (152) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxyoxazol-2-yl)-1,2,3,4,17,18,19,20-octanor-8-azaprost-13-ene, (153) (15α,13E)-1,7-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-methylphenyl)-2,3,4,5,6,17,18,19,20-nonanor-8-azaprost-13-enoic acid, (154) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (155) (15α,13E)-1,5-(2,5-interthienylene)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-2,3,4,17,18,19,20-heptanor-8-azaprost-13-enoic acid, (156) (15α,13E)-3,3-Ethano-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (157) (15α,13E)-1,5-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (158) (15α,13E)-1,5-(1,3-interphenylene)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-2,3,4,17,18,19,20-heptanor-5-thia-8-azaprost-13-enoic acid, (159) (15α,13E)-9-oxo-15-hydroxy-16-(3-(4-fluoromethylbenzyloxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (160) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-3-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (161) (15α,13E)-9-oxo-15-hydroxy-16-cyclopropyl-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (162) (15α,13E)-9-oxo-15-hydroxy-16-phenyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (163) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-carboxythiazol-2-yl-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (164) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-2-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (165) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-4-ylmethoxy)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (166) (15α,13E)-9-oxo-15-hydroxy-16-(3-(pyridin-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (167) (15α,13E)-9-oxo-15-hydroxy-16-cyclopentyl-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (168) (15α,13E)-9-oxo-15-hydroxy-16-(3-(2,2,2-trifluoroethoxymethyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (169) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzofuran-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (170) (15α,13E)-9-oxo-15-hydroxy-16-(5-methylfuran-2-yl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (171) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-5-(6-carboxypyridin-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (172) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid dibutylcarbamoylmethyl ester, (173) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(2,2-diethylpentanoyloxy)ethyl ester, (174) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(adamantan-1-ylcarbonyloxy)ethyl ester, (175) (15α,13E)-9-oxo-15-hydroxy-16-(4-fluorophenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid 2-(1-ethyl-1-methylbutanoyloxy)ethyl ester, (176) (15α,13E)-9-oxo-15-hydroxy-16-(3-methylphenyl)-5-(4-(2-(1-ethyl-1-methylbutanoyloxy)ethoxycarbonyl)thiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprost-13-ene, (177) (15α,13E)-9-oxo-15-hydroxy-16-(3,4-dihydroxyphenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (178) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(2-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (179) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(3-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (180) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (181) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-trifluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (182) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(3,5-ditrifluoromethylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (183) (15α,13E)-1,6-(1,4-interphenylene)-9-oxo-15-hydroxy-16-(3-(4-t-butylphenyl)phenyl)-2,3,4,5,17,18,19,20-octanor-8-azaprost-13-enoic acid, (184) (15α)-9-oxo-15-hydroxy-16-(3-phenylphenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (185) (15α)-9-oxo-15-hydroxy-16-(3-(4-methylphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (186) (15α)-9-oxo-15-hydroxy-16-(3-(4-chlorophenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (187) (15α)-9-oxo-15-hydroxy-16-(3-(4-methoxyphenyl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (188) (15α,13E)-9-oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (189) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (190) (15α,13E)-9-oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (191) (15α)-9-oxo-15-hydroxy-16-(3-(naphthalen-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (192) (15α)-9-oxo-15-hydroxy-16-(3-(benzoxazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (193) (15α)-9-oxo-15-hydroxy-16-(3-(benzothiazol-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, (194) (15α,13E)-9-oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (195) (15α,13E)-9-oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-17,18,19,20-tetranor-5-thia-8-azaprost-13-enoic acid, (196) (15α)-9-oxo-15-hydroxy-16-(3-(isoindolin-2-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, and (197) (15α)-9-oxo-15-hydroxy-16-(3-(indol-5-yl)phenyl)-5-(4-carboxythiazol-2-yl)-1,2,3,4,17,18,19,20-octanor-5-thia-8-azaprostane, or a non-toxic salt thereof, or a cyclodextrin clathrate thereof 